Ferroptosis in Different Pathological Contexts

Hindawi
Oxidative Medicine and Cellular Longevity

Volume 2021, Article ID 5537330, 16 pages
https://doi.org/10.1155/2021/5537330
Review Article
Ferroptosis in Different Pathological Contexts Seen through the
Eyes of Mitochondria
V. Otasevic,1 M. Vucetic,2 I. Grigorov,1 V. Martinovic,1 and A. Stancic 1
1
Department of Molecular Biology, Institute for Biological Research “Siniša Stanković, ” National Institute of Republic of Serbia,
University of Belgrade, Serbia
2
Medical Biology Department, Centre Scientifique de Monaco (CSM), Monaco
Correspondence should be addressed to A. Stancic; [email protected]
Received 20 January 2021; Revised 8 May 2021; Accepted 25 May 2021; Published 8 June 2021
Academic Editor: Stefano Falone
Copyright © 2021 V. Otasevic et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Ferroptosis is a recently described form of regulated cell death characterized by intracellular iron accumulation and severe lipid
peroxidation due to an impaired cysteine-glutathione-glutathione peroxidase 4 antioxidant defence axis. One of the hallmarks of
ferroptosis is a specific morphological phenotype characterized by extensive ultrastructural changes of mitochondria. Increasing
evidence suggests that mitochondria play a significant role in the induction and execution of ferroptosis. The present review
summarizes existing knowledge about the mitochondrial impact on ferroptosis in different pathological states, primarily
cancer, cardiovascular diseases, and neurodegenerative diseases. Additionally, we highlight pathologies in which the
ferroptosis/mitochondria relation remains to be investigated, where the process of ferroptosis has been confirmed (such as
liver- and kidney-related pathologies) and those in which ferroptosis has not been studied yet, such as diabetes. We will bring
attention to avenues that could be followed in future research, based on the use of mitochondria-targeted approaches as anti-
and proferroptotic strategies and directed to the improvement of existing and the development of novel therapeutic strategies.
1. Introduction ways are also the hallmarks of the above-mentioned

diseases [5, 6]. Therefore, targeting mitochondria-mediated
Despite the progress in medicine during recent decades, dis- pathways aimed at manipulating cell death in diseases has a
eases such as cancer, neurodegenerative and cardiovascular promising therapeutic potential and is of immense research
diseases, and ischemic heart and brain injury still have con- interest. Apoptosis, as the major pathway of normal cell turn-
siderable mortality rates worldwide [1]. In particular, worry- over, has been widely and extensively studied from the aspect
ing is the fact that the incidence of these illnesses is globally of targeting mitochondria as a therapeutic strategy and has
on the rise, pointing to an urgent need for the development proven to be an effective target in many diseases (especially
of novel and effective therapies. Although diverse treatment in cancer and neurodegenerative and cardiovascular dis-
strategies have been exploited for each condition, a major eases) [7–10]. Depending on the context, mitochondria-
concern that still exists is deregulated or adverse cell death dependent apoptotic approaches can be aimed at apoptosis
in the affected tissues, the hallmark that connects these induction, as in cancer, or its inhibition, as in neurodegener-
pathologies at the molecular level. Cell destiny (cell death ative and cardiovascular diseases.
and cell survival) is under the tight control of mitochondria Although apoptosis modulation through different strate-
[2–4]. These organelles regulate a variety of vital cellular gies has achieved significant success in the treatment of these
activities, including ATP synthesis, intracellular calcium diseases [8–11], they are still far from being negligible, which
homeostasis, hormone production and responses to hor- suggests that new avenues for the development of clinical
mones, cell differentiation, and cell death [3]. Thus, it is not regimens need to be examined. One such avenue has been
surprising that defects in mitochondrial activity and/or spe- opened with the discovery of a new type of regulated cell
cific alterations in mitochondria-mediated signalling path- death—ferroptosis.
2 Oxidative Medicine and Cellular Longevity
Ferroptosis is a newly detected form of regulated cell levels [12, 28, 32–35]. In the reverse approach aimed at
death characterized by iron-dependent accumulation of lipid sensitizing cancer cells (e.g., hepatocarcinoma) to their
peroxides arising from the iron-catalysed oxidation of poly- demise, the anticancer activity of erastin, an inducer of fer-
unsaturated fatty acids that can be pharmacologically inhib- roptosis, was mediated by mitochondrial pathways that
ited by iron chelators and lipid peroxidation inhibitors [12]. involve voltage-dependent anion channel (VDAC) opening,
It differs from apoptosis in the changes of cell morphology mitochondrial hyperpolarization, consequent increase in
and biochemistry [12–14]. On the other side, the molecular ROS production, and mitochondrial dysfunction [36, 37].
pathways and key players involved in ferroptosis are very In addition, since mitochondrial morphology and functional
similar, if not identical to those involved in the induction/ activity coexist in an intimate structure/function relationship
mediation of oxytosis or oxidative stress-induced pro- [38–40], along with the characteristic phenotype of mito-
grammed cell death as defined by Tan et al. [15] almost one chondria in ferroptotic cells, mitochondrial function in fer-
decade before ferroptosis. Lewerenz et al. [16] and Maher roptosis is compromised [27, 31] and rescuing or damaging
et al. [17] have suggested that oxytosis and ferroptosis are mitochondrial function can affect the outcome of ferroptosis.
two names for the same cell death pathway reviewing the Taking all these considerations into account in addition
strong evidence for their assertion. Extensive research into to the well-known contributing role of mitochondria to
the process of ferroptosis during the last few years has many different pathologies, we have reviewed the existing
revealed that it is linked to different pathological states, such knowledge of the role of these organelles in the process
as cancer, neurodegenerative, cardiovascular, and hemato- of ferroptosis in disease states, primarily in cancer and
logic diseases, and ischemia/reperfusion (I/R) injury of vari- neurodegenerative and cardiovascular diseases. We will
ous organs, including the heart, brain, and kidney [18–23]. also discuss the potential implementation of specific
Thus, modulating ferroptosis, either by targeted induction mitochondria-targeted approaches for modulating ferropto-
(e.g., cancer) or by its prevention (e.g., in neurodegenerative tic cell death beyond these diseases and in other pathological
and cardiovascular diseases), might be a promising thera- conditions that are accompanied by increased cell death
peutic approach, and together with apoptosis modifiers, and/or impaired mitochondrial function. Finally, we will
this has contributed to better understanding of all the present future directions in the examination of various
above-mentioned diseases and improvement of their treat- mitochondria-targeted approaches for modulating (through
ment. The antipathological rationale is supported by the either induction or suppression) ferroptosis with the aim of
effects of inducers (erastin, Ras-selective lethal small mole- improving the understanding and targeted therapy of the
cule (RSL)) and inhibitors (ferrostatin-1, liproxstatin-1) of discussed diseases.
ferroptosis that have been developed thus far, which can suc-
cessfully modulate cell death in cancer and neurodegenera- 2. Ferroptosis: The Basic Signalling
tive and cardiovascular diseases [22, 24]. At the same time, Pathways and Its Hallmarks
the ability to specifically target mitochondrial pathways to
modulate ferroptosis is less exploited. The reason for this lies Ferroptosis is an iron-dependent, lipid peroxide-driven form
in the fact that in contrast to the well-defined roles of mito- of cell death that differs from other forms of regulated cell
chondria in the regulation of apoptosis, their role in the fer- death with respect to the biochemical pathways, the main
roptotic type of cell death is less well defined [25, 26]. In triggers and executors, and morphological features. Since
addition, the results of studies investigating the relationship 2012 when the Stockwell Group first recognized ferroptosis
between mitochondrial functionality and ferroptosis are con- as a new form of cell death, evidence in support of its unique-
troversial [12, 20, 27–29], and the lack of consensus as to ness has increased [12]. The main event in ferroptosis is the
their actions keeps the debate open. uncontrolled accumulation of lipid peroxides as a result of
However, the recently revealed molecular mechanisms of an imbalance in their production and removal. Two major
ferroptosis show that the involvement of mitochondria in the pathways lead to lipid peroxide formation: enzymatic and
regulation of this type of cell death has become more impor- nonenzymatic [41]. The former involves enzymes that catal-
tant and points to further directions in research. yse the metabolism of arachidonic acids and polyunsaturated
Specifically, the crucial role of mitochondria in lipid fatty acids (PUFAs), with the central role assumed by lipox-
peroxidation-driven ferroptotic cell death has been observed ygenases (LOXs). The latter is a redox-based mechanism of
in the following conditions: (i) impaired mitochondrial lipid peroxide production. This process is triggered when
metabolism and ensuing extensive production of reactive ROS, reactive nitrogen species (RNS), or reactive lipid species
oxygen species (ROS), (ii) excess free-iron accumulation in (RLS) extract a hydrogen atom from a PUFA, forming a lipid
mitochondria, and (iii) mitochondrial cysteine deprivation radical (L∙) [41]. The hydroxyl radical (∙OH) and the hydro-
[27, 28, 30]. Along these lines, the prevention of these mito- peroxyl radical (∙OOH) are the strongest initiators of this
chondrial states significantly correlates with increased resis- process. They are formed in the reaction of ferrous iron
tance to ferroptotic cell death [28, 30–32]. Great progress (Fe2+) with hydrogen peroxide (H2O2) in the Fenton reaction
has been made in the protection of cardiomyocytes and [41]. Regardless of the pathways that lead to the initiation of
neuronal cells from the inducers of lipid peroxidation and lipid peroxidation, this process moves on to the second and
ferroptosis by blocking mitochondria-dependent ferroptosis third phases, propagation and termination, respectively
pathways using specific mitochondria-targeted ROS scaven- [42]. In the propagation phase, L∙ rapidly reacts with oxygen
gers, antioxidants, and modulators of mitochondrial iron to form a lipid peroxy radical (LOO∙), which extracts a
Oxidative Medicine and Cellular Longevity 3
hydrogen atom from another lipid molecule, generating a that targeting of the system xCT plays a major role in the pro-
new L∙ (which continues the chain reaction) and a lipid cess of ferroptosis induction by erastin [12]. However, the
hydroperoxide (LOOH) [41]. Once lipid peroxidation is ini- effect of erastin on VDAC is relevant in the context of the role
tiated, propagation of chain reactions occurs until the termi- of mitochondria in ferroptosis, as discussed above. Besides
nation products are produced. The lipid peroxides produced these pharmacological approaches that target xCT and
during the propagation phase can be converted into hydroxy cystine/glutamate metabolism, natural triggers that induce
fatty acids or reactive aldehydes that initiate lipid peroxida- ferroptosis in physiological contexts have been described.
tion themselves and thus the chain reaction [42]. One is the accumulation of extracellular glutamate [12, 20].
However, it is unclear how lipid peroxidation leads to fer- Glutamate-induced toxicity has been extensively studied in
roptotic cell death. It is likely that cell death is the result of HT22 cells, a specifically designed mouse hippocampal nerve
multiple events, including direct damage to specific mem- cell line that is particularly sensitive to glutamate and is killed
branes and the activation of downstream pathways [43–45]. exclusively via the oxidative pathway called oxytosis [61].
Membrane lipid peroxidation induces its disruption and The first step in this cell death is glutamate-induced inhibi-
changes physical properties, decreasing membrane fluidity, tion of cystine uptake through xCT [62]. The same pathway
increasing membrane permeability, disturbing the ion of glutamate-induced cell death has been recently described
gradient, and slowing down lateral diffusion [46–49]. in the context of ferroptosis [63, 64]. The second “natural”
Furthermore, the formation of secondary products of lipid approach that can induce ferroptosis is cystine deprivation,
peroxidation of PUFAs can modulate protein functions and which triggers ferroptosis through GSH depletion [27, 65].
several signalling pathways that interfere with cell death Gao et al. [27] showed that a cysteine-free medium induces
[50, 51]. Among these, malondialdehyde (MDA) and 4- cysteine and GSH depletion and results in ferroptosis of the
hydroxynonenal (4-HNE) are the most abundant and HT1080 cell line.
exhaustively studied in the context of other types of cell Ferroptosis can also be pharmacologically induced by
death, apoptosis and necrosis [52]. It was shown that these inhibition of GPX4 activity with the commonly used
aldehydes accumulate in different models of ferroptosis inhibitor RSL [59]. Also, the suppression of GSH synthesis
[14, 53, 54], but their significance in this type of cell death by GCL inhibition with buthionine sulfoximine (BSO) in
needs to be defined. some cases represents a successful approach in ferroptosis
Under basal conditions, the lipid peroxidation cascade is induction [55].
controlled by the antioxidant enzyme glutathione peroxidase In addition, an important regulatory point and therefore
4 (GPX4) that uses glutathione (GSH) to reduce lipid perox- a target for ferroptosis modulators is the metabolism of iron,
ides to their alcohol form (LOOH). GSH-GPX4, or more which is, as previously mentioned, a crucial player in the ini-
precisely the axis involving cysteine-GSH-GPX4-lipid per- tiation of lipid peroxidation (Fenton reaction). Thus, the
oxides, constitutes the backbone of ferroptosis signalling imbalance of intracellular iron homeostasis in favour of iron
[55]. GSH is a simple tripeptide with cysteine playing an overload is pivotal in the induction of ferroptosis [33, 66, 67],
important role in redox state regulation due to its reactive while iron chelators such as deferoxamine (DFO) have been
thiol. In addition to its role as a cofactor for GPX, two used for its inhibition [35, 68]. The molecular machinery
more aspects of GSH action are relevant to ferroptosis: dedicated to ferroptosis with possible targets for its modula-
(i) regulation of the activity and intracellular translocation tion is presented in Figure 1.
of LOXs [15, 56] and (ii) the redox cycling activity of Fe2+ Morphological changes related to ferroptosis also make
[45, 57]. Depletion of GSH increases both LOX activity this type of cell death unique and recognizable when com-
and membrane translocation as well as the substrate of pared to other types of cell death—apoptosis, necrosis, and
the Fenton reaction. Also, GSH is a cofactor for glutathi- autophagy. Ferroptosis is characterized by the so-called “bal-
one S-transferase (GST) in the reaction of detoxification looning” phenotype [69, 70], observed as a characteristic
of both ROS and xenobiotics [58]. rounded morphology of the cell surface. This seems to be
Cells obtain cysteine from the extracellular environment the result of several morphological alterations, including
in the oxidized (dominant) form, cystine, through the cysti- destabilization of the plasma membrane, disturbed proteos-
ne/glutamate antiporter, xCT. In the cell, cystine is reduced tasis, and rearrangement of the cytoskeleton [71–73]. Also,
to cysteine via cysteine reductase and “incorporated” into ferroptotic cells exhibit extensive ultrastructural changes in
GSH through enzymatic reactions catalysed by glutamate- the mitochondria, with the mitochondria being smaller than
cysteine ligase (GCL) and glutathione synthetase (GSS). Con- normal with an increased bilayer membrane density [12, 37].
sequently, one approach for ferroptosis induction involves There are reduction in volume, disruption of the outer
the targeting of xCT. Erastin has been widely used as a phar- mitochondrial membrane, and loss of mitochondrial cristae
macological modulator/inducer of ferroptosis [59]. Initially, [44, 69]. This is clearly different when compared to apoptosis,
erastin was described as an antitumor compound that where no significant changes in mitochondrial structure
induces cell death in RAS-overexpressing cells [60]. Subse- are observed, and to necrosis, in which the swelling of
quently, it was reported that erastin exhibits an inhibitory organelles, including the mitochondria, has been observed
activity over VDAC [37] and xCT [12]. Although both these [23]. In addition, none of the characteristic morphological
actions of erastin are related to ferroptosis induction, it is features related to necrosis (cytoplasmic swelling, plasma
likely that inhibition of VDAC2 and VDAC3 is necessary membrane rupture), apoptosis (chromatin condensation
but not sufficient for erastin-induced death [37]. It is believed and margination), or autophagy (formation of double-
Cystine Glutamate
Erastine, sulfasalazine
BSO Cystine xCT
Ferritin
4
OA DFO
NC
Ferritinophagy
2+
Cysteine Fe
ST
E
TFR1
GCL AP
3 Transferrin-Fe3+
Glutathione (GSH) DMT1 Fe3+
H2O2
NAC
Ub
GSSG Se GPX4
iqu Fenton
ino
l RSL3
FS
UbP1
ol
iqu
in
qu
ino
bi
ne
U
Lipid peroxidation
Vitamin E, ferrostatin-1
FERROPTOSIS
Figure 1: The main cellular pathways related to ferroptosis and potential targets for its manipulation (induction or inhibition). The main
regulatory pathway of ferroptosis involves the cysteine-GSH-GPX4-lipid peroxide axis. Cysteine is transported into the cell via xCT in its
oxidized form (cystine). One of the main roles of cysteine is the synthesis of glutathione (GSH), a process in which the key-limiting step is
catalysed by glutamate-cysteine ligase (GCL). GSH serves as a cofactor of glutathione peroxidase 4 (GPX4), which reduces lipid peroxides
to their alcohol form. Alternatively, lipid peroxides can be reduced by ubiquinol residing in the membrane compartments of the cell. In
this way, produced ubiquinone is reduced back to its alcohol form by the action of ferroptosis-suppressor protein 1 (FSP1). The central
event in the lipid peroxide production pathway is the Fenton reaction, a reaction between Fe2+ and H2O2. The iron is imported into the
cell as an iron-loaded transferrin-transferrin receptor 1 (TFR1) complex via receptor-mediated endocytosis. In the endosome (an acidic
environment), free Fe3+ is converted to Fe2+ by the transmembrane metalloreductase STEAP3 and released into the cytoplasm via the
divalent metal transporter 1 (DMT1). Red arrows represent potential activators of ferroptosis: (i) inhibitors of xCT (erastin, sulfasalazine),
(ii) the inhibitor of GSH biosynthesis and GCL (buthionine sulfoximine (BSO)), and (iii) the inhibitor of GPX (Ras-selective lethal 3
(RSL3)). Green arrows represent potential ferroptosis inhibitors: (i) alternative source of cysteine (N-acetylcysteine (NAC)) and (ii) lipid
peroxide scavengers (vitamin E, ferrostatin-1). This figure was created using Servier Medical Art templates, which are licensed under the
Creative Commons Attribution 3.0 Unported License (https://smart.servier.com).
membrane enclosed vesicles) have been associated with and its distinction from other types of cell death [12], as we
ferroptosis [12, 13, 19, 36]. stated above, the contribution of mitochondrial metabolism
The fact that ferroptosis cannot be inhibited by the clas- to the triggering and execution of ferroptosis is still a matter
sical inhibitors of apoptosis, autophagy, and necrosis [44] of debate. Several aspects of mitochondria-related metabo-
establishes the uniqueness of ferroptosis, not only from apo- lism predispose this organelle to the induction of ferroptosis,
ptosis but also from other types of cell death. including metabolism of energy substrates (especially lipids)
and accompanying ROS production, as well as the metabo-
3. Mitochondria-Dependent lism of amino acids (glutamine) and iron (summarized in
Pathways in Ferroptosis Figure 2).
Mitochondria play an important role in lipid metabolism.
Although knowledge about the mechanisms mediating fer- Citrate synthase (CS) and acyl-CoA synthetase family mem-
roptosis is constantly growing, there is still no consensus ber 2 (ACSF2), which are localized in the mitochondria, reg-
regarding the specific contribution of each organelle to the ulate fatty acid activation and synthesis and thus provide
initiation and execution of this type of cell death. Current precursors for lipid peroxidation. These enzymes have been
data argue that lipid peroxidation localized in the endoplas- recognized as important mediators of erastin-induced fer-
mic reticulum, lysosomes, Golgi apparatus, and mitochon- roptosis [12]. In addition to fatty acids, the metabolism of
dria can be involved in signalling related to ferroptosis [20]. glutamine, a nonessential amino acid, might provide precur-
As an integrative place for many intracellular and sors for the tricarboxylic acid (TCA) cycle, especially in states
extracellular signals, the mitochondria play a central role in of increased metabolic demand such as cancer [74]. Enzymes
determining cell destiny [3]. Their essential role in the regu- important for the catalysis of glutaminolysis are localized
lation of apoptosis and necrosis has been confirmed through in the mitochondria. Regardless of the source of the pre-
decades of examination of these types of programmed cell cursors, the increase in TCA and oxidative phosphorylation
death [3, 4]. Although changes in mitochondrial morphology (OXPHOS) leads to ROS accumulation in the mitochondria,
represent one of the criteria for the definition of ferroptosis which supports their active role in triggering ferroptosis [75].
Fatty acid
biosynthesis
Fe2+ Acetyl-CoA Fatty acids PUFA
Fatty acyl-CoA
MFRN
Mitochondrial
ferritin
AC 2
Krebs
Fatty acids
SF
cycle
N
I
FS
Mt
1
-LO ROS I
II I
H
Q Q ROS II ISC
? FSP1 III Q II
ROS Fenton Q
Q reaction III
IV III
M
t-L
IV
GP×4 IV
OO
V Glu Gln Gln
ABCB7
H
V V Y Glutaminolysis
Mt-LOOH
ROS VDAC
ROS ROS
Figure 2: Potential mitochondrial targets for ferroptosis manipulation. Mitochondrial oxidative phosphorylation (OXPHOS) is the main
cellular source of reactive oxygen species (ROS). In the presence of ferrous ions (Fe2+), ROS can induce the production of lipid peroxides
(LOOH) in the membrane compartment of the mitochondria (Fenton reaction), thereby compromising the structure and function of the
cellular powerhouse and leading to further propagation of oxidative damage within the cell. The transport of iron ions into mitochondria
is achieved by mitoferrin-1/2 (MFRN), a member of the mitochondrial solute carrier family of proteins. Once inside the mitochondria,
ferrous ions are used for many different purposes, such as the synthesis of heme or iron-sulphur clusters (ISCs) and key prosthetic groups
of a variety of enzymes, including the TC complexes. From the standpoint of ferroptosis, the NFS1 and ABCB7 transporters, respectively,
responsible for the synthesis and export of ISCs from the mitochondria to the cytosol appear to be important (see text). The excess of free
iron is sequestered in mitochondrial ferritin to prevent potentially harmful effects of iron-induced oxidative damage. One possibility
which remains to be examined is the potential antioxidant role of ubiquinol and ferroptosis-suppressor protein 1 (FSP1) against
accumulated LOOH in the mitochondrial membrane compartment (the question mark in the scheme). The presence and protective role
of glutathione peroxidase 4 (GPX4) at the side of cytochrome c release have been shown. Aside from the classical redox active species,
mitochondrial metabolic intermediates appear to be involved in cell destiny, pushing it towards ferroptosis. The mitochondria-localized
tricarboxylic acid (TCA) cycle is a central hub regulating fatty acid breakdown and synthesis, as well as the flux through OXPHOS. Thus,
the TCA cycle could be seen as the major regulating point of ferroptosis through (i) the regulation of ROS production, (ii) the regulation
of ATP production, and (iii) the regulation of the production of the precursors (acetyl-CoA units) for the synthesis of ferroptosis
executors—polyunsaturated fatty acids (PUFA; #NB: the regulation of acetyl-CoA incorporation into fatty acids is regulated by
cytoplasmic enzymes). The voltage-dependent anion channel (VDAC), as one of the central players in the import/export of many different
ions/metabolites (X/Y), energy regulation, and ion and intermediate balance across two sides of the mitochondrial membrane, also
appears to be involved in the regulation of ferroptosis (see text). ACSF2: mitochondrial medium-chain acyl-CoA ligase; Glu: glutamate;
Gln: glutamine. This figure was created using Servier Medical Art templates, which are licensed under the Creative Commons Attribution
3.0 Unported License (https://smart.servier.com).
The electron transport chain- (ETC-) mediated ROS produc- rate dehydrogenase, and α-glycerophosphate dehydrogenase
tion has been described as important for cell death in the [79] could contribute to increased ROS production in mito-
state of GSH depletion, such as treatment with glutamate chondria. These enzymes have been proposed as mediators
and cystine deprivation [15, 27, 76]. Tan et al. [15] have of RSL3-induced ferroptosis since RSL3 increases the level
shown that ROS production and the death of HT22 cells of the mitochondrial-specific ROS probe MitoSOX [25, 35],
induced by glutamate (subsequently named oxytosis) can but this effect is not inhibited by ETC inhibitors [27].
be inhibited by ETC inhibitors or uncouplers (FCCP, car- Mitochondria also play an important role in iron metab-
bonyl cyanide-p-(trifluoromethoxy) phenylhydrazone) that olism. There are several iron homeostasis-regulating mole-
dissipate the mitochondrial membrane potential [77]. cules in the mitochondria, including mitoferrin, the ABC
Similar changes have been shown recently in the case of fer- transporter, and VDAC, all of which have been connected
roptosis induced by cystine depletion [27]. Important data to ferroptosis (reviewed by Wang et al. [26] and Battaglia
relevant to this issue were published recently by Homma et al. [65]). VDAC is an important mitochondrial porin that
et al. [30]. The authors provided direct evidence that the regulates the influx and efflux of many mitochondrial metab-
superoxide anion radical produced by complex III is pivotal olites in addition to iron and thereby several aspects of mito-
for cysteine starvation-induced ferroptosis; they found that chondrial metabolism, including mitochondrial membrane
the specific inhibitor of complex III, but not of complex I, potential, Ca2+ overload, and ROS production [80]. VDAC
protects mouse hepatoma Hepa 1-6 cells from ferroptosis has been recognized as a target of some antiferroptotic
in this condition. approaches such as erastin, erastin-like lead compounds
In addition to the nonenzymatic production of ROS in [36, 37], and RSL5 [81]. Cells expressing more VDAC pro-
OXPHOS, some enzymes localized in the mitochondria such tein were more sensitive to erastin [36]. Calcium chelators
as monoamine oxidase, NADPH oxidase 4 [78], α-ketogluta- effectively counteract erastin-induced cell death in LUHMES
cells [82], confirming hyperpolarization of the mitochondrial the resistance of cancer cells to regulated types of cell death,
membrane in ferroptosis. It was also shown that the suppres- especially apoptosis [92]. Considering the multifaceted role
sion of two genes encoding the critical steps of mitochondrial of mitochondria in cancers (reviewed in Badrinath and Yoo
iron-sulphur cluster (ISC) biosynthesis, NFS1 and ABCB7, [93]), more mitochondria-based cancer therapies are needed
leads to an increase in intracellular free iron and promotes to guarantee fully beneficial outcomes in cancer treatment. In
cell death by ferroptosis [83]. that context, the involvement of mitochondria and mito-
Apart from the pathways connected to the fundamental chondrial metabolism in ferroptosis deserves more attention.
role of mitochondria in cells, there are some specific factors In the initial characterization of ferroptosis, Dixon et al.
that might link mitochondria and ferroptosis. One of these [12] reported that mitochondrial DNA- (mtDNA-) depleted
is BID, a proapoptotic protein of the Bcl-2 family, whose ρ0 (Rho0) cells remained sensitive to oxidative stress and
translocation into the mitochondria has been shown to medi- ferroptosis induction in the fibrosarcoma cell line, HT1080.
ate erastin-induced ferroptosis in neuronal cells [25]. Also, This was confirmed in their work on mitochondria-
the flavoprotein apoptosis-inducing factor mitochondria- depleted HT1080 cells generated by a mitophagy protocol
associated 2 (AIFM2) has recently been recognized as an [29, 94]. These cells exhibited similar sensitivity to
important antiferroptotic factor involved in maintaining the ferroptosis-modulating agents (the inducers erastin and
antioxidant activity of coenzyme Q in the membrane com- RSL1 and inhibitors ferrostatin-1 and iron chelators) as their
partment of the cell and has been renamed ferroptosis sup- counterparts harbouring mitochondria. Furthermore, Ye
pressor protein 1 (FSP1) [14, 84]. It is interesting to note et al. [95] showed that erastin-induced ferroptosis in a leu-
that FSP1 could be seen as an alternative to the GSH-GPX4 kaemia cell line did not involve changes in mitochondria-
part of the ferroptosis-regulating axis, providing protection mediated ROS generation. Although the data suggest that
against the accumulation of lipid peroxides even in condi- mitochondria are not required for cancer-associated ferrop-
tions of GSH depletion [70]. tosis, these results are somewhat surprising considering all
Growing evidence points to the relevance of oxidation of the above-discussed aspects of mitochondrial metabolism
the mitochondrial membrane in ferroptosis induction/execu- that should interfere with the ferroptotic process.
tion [19, 28]. Friedmann Angeli et al. [19] provided direct It is likely that contradictory results on the involvement
evidence that the oxidation of mitochondrial membranes is of mitochondria in ferroptosis are due to different methods
important for the execution of ferroptosis. They found an for measuring both mitochondrial function and cell death,
accumulation of oxidized mitochondria-specific phospho- as well as differences between cancer cells. Using Rho0 cells
lipid cardiolipin in the kidney of GPX4-knockout mice. In might not be the best method for investigating the signifi-
this context, mitochondrially localized GPX4 plays an impor- cance of mitochondria in cell death processes because Rho0
tant role in protection from ferroptosis [85]. The presence of cells are generated by long-term cultivation with ethidium
GPX4 in mitochondria at the side of cytochrome c release bromide that frequently induces damage of nuclear DNA
and its protective role in apoptosis have been previously [96]. This could affect the response of the cells to oxida-
shown [86]. tive stress-inducing agents, including different ferroptosis
inducers. Furthermore, it seems likely that there are dif-
4. The Role of Mitochondria in Ferroptosis ferences between various Rho0 cancer cell lines in their
Induction in Cancer sensitivity to ferroptosis. In contrast to the Rho0 fibrosar-
coma cell line that shows similar sensitivity to ferroptosis-
The possibility to interfere with ferroptosis signalling path- inducing agents to that of parental cells (as described above
ways and to manipulate this type of cell death might be of and in Dixon et al. [12]), Rho0 cells established from human
great importance in cancer therapy. There is hope among cervical cancer and oral squamous cell carcinoma cell lines
cancer researchers that ferroptosis induction could be a suc- display more sensitivity to H2O2-induced ferroptosis, along
cessful anticancer approach since many cancer types that are with increased levels of ∙OH, Fe2+, and lipid peroxidation
resistant to conventional chemotherapy appear to be sensi- [97, 98]. These results have highlighted the relevance of mito-
tive to ferroptosis [87, 88]. An important example is pancre- chondrial dysfunction in ferroptosis induction in cancer and
atic ductal adenocarcinoma (PDAC) that is resistant to many must be considered during the development of new antican-
cancer therapies. As was recently reported in in vitro and cer ferroptosis-based approaches.
tumour xenograft studies [68, 89], the inhibition of xCT Increasing evidence suggests that mitochondrial metabo-
either with erastin or by genetic ablation sensitizes PDAC lism may be of functional relevance to ferroptosis progres-
cells to ferroptosis and could thus present a promising thera- sion and final execution in cancer cells. For example, acyl-
peutic strategy for this type of cancer. It is likely that the sen- CoA synthetase long-chain family member 4- (ACSL4-) dic-
sitivity of cancers to common genetic or pharmacological tated ferroptosis in breast cancer cells is accompanied by
approaches for manipulation of ferroptosis differs between changes in mitochondrial morphology [14]. Literature also
various types of cancer, with the highest sensitivity observed suggests that erastin-induced anticancer activity might be
in brain tumours [90, 91]. However, the precise mechanisms mediated by mitochondria [36, 37]. For example, DeHart
that determine the sensitivity of cancer cells to ferroptosis et al. [36] have shown that erastin-induced cell death in a
induction are not fully elucidated. On the other hand, it is hepatocarcinoma cell line involves VDAC opening and mito-
well known that mitochondria underlie the phenotypic and chondrial hyperpolarization, followed by increased ROS pro-
metabolic plasticity of cancer cells and are responsible for duction, mitochondrial dysfunction, and finally a collapse of
the transmembrane potential. Using RNAi-based loss-of- nisms of cardiomyocyte ferroptotic cell death appear to
function screening in lung cancer cell cultures and tumour involve mitochondria-dependent pathways [31, 33]. This is
xenografts, Alvarez et al. [83] showed that the suppression quite reasonable considering that mitochondria have previ-
of two genes encoding critical steps of mitochondrial ISC bio- ously been described as essential to proper cardiomyocyte
synthesis, NFS1 and bcl7, leads to iron release from intracel- functioning [103, 104].
lular stores and promotes cell death by ferroptosis. ISCs, as A study performed by Fang et al. [33] demonstrated that
critical components of the OXPHOS complexes and many the increase in free iron as the result of heme degradation
other metabolic enzymes, are fundamental to the normal drives ferroptosis of cardiomyocytes in apoptosis- and/or
functioning of mitochondria, especially at high concentra- necroptosis-defective Ripk3-/-, Mlkl-/-, or Fadd-/-Mlkl-/- mice
tions of O2. The downregulation of NFS1 (i) induces loss of exposed to the DNA-damaging agent doxorubicin or in the
essential cell functions due to cofactor depletion and (ii) sen- I/R condition. It was shown that excess free iron accumulates
sitizes cells to ferroptosis by activating the iron starvation in the mitochondria, not in the cytoplasm, and causes lipid
response and iron overload. peroxidation specifically in mitochondrial membranes. The
It was recently shown that the mitochondria only play a authors further showed that the inhibition of pathways that
role in cysteine deprivation-induced ferroptosis but not in mediate mitochondria-driven ferroptosis (after treatment
ferroptosis induced by GPX4 inhibition [27]. As the authors with a specific mitochondria-targeted antioxidant, Mito-
explained, this is probably because the mitochondrial func- TEMPO) significantly ameliorated doxorubicin-induced
tion upstream of GPX4 promotes the exhaustion of GSH lipid peroxidation and cardiac ferroptosis. Moreover, Mito-
under cysteine deprivation conditions. In contrast to Dixon’s TEMPO but not TEMPO, a nonspecific antioxidant, signifi-
laboratory, Gao et al. [27] observed that depletion of the cantly reduced doxorubicin-induced cardiomyopathy,
mitochondria through parkin-mediated mitophagy or inhi- assessed by measuring the heart/body weight ratio, serum
bition of OXPHOS dramatically decreased the sensitivity of levels of myocardial enzymes, and cardiac hypertrophy bio-
cells to cysteine deprivation-induced ferroptosis in a human markers. These data clearly showed that oxidative damage
fibrosarcoma cell line. Their work also highlighted the of mitochondria is the major consequence of iron overload
importance of glutaminolysis as an indispensable part of cys- in I/R-induced heart damage and suggest that the decrease
teine deprivation-induced ferroptosis. In most cancer cells, in mitochondrial iron accumulation and/or inhibition of
the rate of glutaminolysis is increased to meet their bioener- lipid peroxidation may be cardioprotective during both acute
getic requirements [73]. However, this could make cancer and chronic cardiac I/R.
cells more vulnerable to ferroptosis induction. Under cyste- Apart from the above-described role of mitochondria in
ine deprivation, glutaminolysis promotes mitochondrial res- cardiac I/R injury-associated cardiomyocyte ferroptosis,
piration and rapid exhaustion of GSH by GPX4, rendering another study performed by Feng et al. [31] revealed addi-
these cells dependent on the cysteine-GSH supply and thus tional mitochondria-dependent mechanisms that could be
prone to ferroptosis. Recently published data also speak in involved in the execution of ferroptosis. The authors
favour of the significance of mitochondrial metabolism in showed that postischemic application of liproxstatin-1 to
the execution of ferroptosis in cancer cells. Namely, it has the mouse myocardium decreased I/R injury, as shown by
been suggested that the rerouting of tumour cell metabolism the decreased size of the infarct-affected area. Importantly,
from glycolysis to OXPHOS could make cells more vulnera- they found that the observed cardioprotective effects of
ble to GSH depletion and ferroptosis [99]. liproxstatin-1 were achieved through maintenance of mito-
A significant amount of data suggests that mitochondria chondrial structural and functional integrity. The precise
and mitochondria-related signalling could be a promising mechanism of the beneficial effects of liproxstatin-1 on
target in terms of ferroptosis induction as an anticancer ther- mitochondria involves the reduction of VDAC1 level and
apeutic strategy. However, further studies are needed to its oligomerization, without affecting VDAC2/3, as well as
establish specific targets and approaches for their manipula- a decrease in mitochondrial ROS production by the ETC
tion, as well as the specificity and sensitivity of different complex I (NADH:ubiquinone oxidoreductase). These
tumours to such manipulations. results are in agreement with studies postulating that mito-
chondrial ROS generation is a significant contributor to
5. Mitochondria and Ferroptosis in ferroptosis [105, 106]. This contrasts with the often-
Cardiovascular Diseases represented standpoint that mitochondrial damage is a sec-
ondary event in ferroptosis [13, 80] and also opposes stud-
Myocardial infarction and heart failure are cardiovascular ies that did not observe changes in complex I ROS
diseases with the highest mortality rates worldwide [10]. A production in erastin-induced or ferrostatin-inhibited fer-
crucial pathogenic factor in the development of both pathol- roptosis [12, 63], suggesting that the impact of mitochon-
ogies is the loss of terminally differentiated cardiomyocytes drial ROS on ferroptosis might be dependent on the
[10, 100, 101]. Pharmacological and genetic manipulations specific inducer or inhibitor of ferroptosis used. In any case,
indicate that cardiomyocyte cell death is the central event the results of Feng et al. [31] revealed the antiferroptotic
in the pathogenesis of both diseases [10, 100, 101]. In addi- and cardioprotective effects of liproxstatin-1 via direct
tion to apoptosis and necrosis, ferroptosis has recently mitochondrial pathways.
emerged as an important cause of cardiomyocyte death, at These discoveries raise the possibility of attenuating car-
least in I/R heart injury [31, 33, 102]. Moreover, the mecha- diomyocyte cell death through the manipulation of the
mitochondrial signalling pathways and may provide novel enger mitoquinone (MitoQ) preserved mitochondrial integ-
therapies for common and highly lethal heart diseases. rity and function, as well as cell viability despite significant
loss of GPX4 expression accompanied by an increase in gen-
6. Mitochondria and Ferroptosis in eral lipid peroxidation after exposure to RSL3.
Neurodegenerative Diseases Apart from the in vitro data indicating that rescuing
mitochondrial integrity and function might be effective in
All neurodegenerative diseases are characterized by the pro- the prevention of ferroptosis in neural cells, the involvement
gressive and irreversible loss of neurons from specific regions of mitochondria and ferroptosis in neurodegenerative dis-
of the central and peripheral nervous systems, followed by a eases has been supported by results obtained in studies per-
decline in neuronal, motor, and/or cognitive functions formed in vivo on experimental animals [113–115]. It was
[107]. It was shown that cellular death driven by increased shown that the expression of all three GPX4 isoforms is
levels of iron, ROS, and consequent lipid peroxidation—fer- reduced in both the brain of multiple sclerosis patients and
roptosis—is an important contributor to neural cell death the spinal cord of animals with an experimental autoimmune
in Alzheimer’s, Parkinson’s, and Huntington’s diseases, mul- encephalomyelitis (EAE) [115]. The detected decrease in
tiple sclerosis, and acute brain injury caused by cerebral GPX4 in EAE was accompanied by morphological changes
ischemia, haemorrhagic insults, or brain trauma [108–111]. in the mitochondria characteristic for ferroptosis, including
In addition, more recent studies have suggested that mito- an irregular matrix, disrupted outer membrane, and reduced
chondrial damage might be the ultimate step in ferroptosis- or absent cristae [115]. In addition, in the experimental
related oxidative cell death in neurodegeneration [112]. It model of arsenite-induced neuronal cell death that was
was shown that brain regions with the highest levels of iron shown to be associated with various neurodegenerative dis-
and ROS accumulation are associated with excessive mito- eases such as Alzheimer’s and Parkinson’s, as well as amyo-
chondrial damage, clearly linking the loss of mitochondrial trophic lateral sclerosis (ALS), it was shown that the loss of
integrity and function to oxidative neuronal death and neu- neurons is caused by the accumulation of ROS and character-
rodegeneration [112]. istic ferroptotic events, including mitochondrial VDAC-
The first suggestion that the process of ferroptosis in neu- related pathways [114]. Although specific identification of
rodegenerative diseases is regulated by mitochondria came ferroptosis in vivo is hampered by lack of specific biomarkers,
from the research of Gao and Chang [21] who showed the it was shown that conditional ablation of GPX4 to the
involvement of mitochondrial ferritin in the regulation of forebrain neurons of adult mice causes hippocampal degen-
brain iron homeostasis and oxidative neuronal cell death, eration resembling Alzheimer’s disease and cognitive impair-
while Wang et al. [32] demonstrated the protective role of ments accompanied by lipid peroxidation and mitochondrial
mitochondrial ferritin in erastin-induced ferroptosis. Iron impairments consistent with ferroptosis [113]. This can be
accumulation in mitochondria is also found in ferroptosis partly rescued by inhibitors of ferroptosis, confirming ferrop-
related to Friedreich’s ataxia where the mitochondria- tosis involvement.
targeted antioxidant XJB-5-131 was found to be effective in All the above data indicate that rescuing mitochondrial
inhibiting ferroptosis [34]. integrity and function might be effective in the prevention
The involvement of mitochondria in neurodegeneration- of ferroptosis in neural cells and provide a new approach in
associated ferroptotic cell death is further demonstrated in targeting cell death in neurodegenerative conditions. There-
PC12 cells where the induction of ferroptosis by tert-butyl fore, mitochondria-dependent mechanisms of ferroptosis in
hydroperoxide (t-BHP) was accompanied by a decrease in the nervous system need to be fully explored in future
the mitochondrial membrane potential, decreased ATP pro- research.
duction, and an increase in mitochondrial ROS [112]. More-
over, in the same model system, it was observed that apart 7. Ferroptosis in Other Pathologies and the
from suppressing ferroptosis, ferrostatin-1 also “repaired” Involvement of Mitochondria
mitochondrial dysfunction, strongly indicating that mito-
chondrial dysfunction is closely related to ferroptosis [112]. The list of pathologies that involve ferroptosis as an underly-
These results are in line with the data of Jelinek et al. [35] ing mechanism of their aetiology and progression is growing,
who reported that in addition to ferrostatin-1, other ferrop- as is knowledge about the signalling pathways regulating this
tosis inhibitors are also capable of preventing mitochondrial type of cell death. In this context, ferroptosis has been estab-
damage in neuronal HT-22 cells and of decreasing ferropto- lished as a contributing factor to tissue damage in ischemic
sis induced by RSL3-dependent inhibition of GPX4 and the injury of the kidney and in liver diseases [18, 19, 63], in addi-
generation of damaging free radicals. The authors [35] estab- tion to the previously described contribution of apoptosis
lished that in neuronal HT22 cells, RSL3 mediates the and necrosis [116–119]. Ferroptosis is also involved in liver
concentration-dependent inhibition of GPX4 followed by lipid haemochromatosis [120] and mediates the activity of anti-
peroxidation, enhanced mitochondrial fragmentation, reduc- cancer drugs commonly used in hepatocellular cancer ther-
tion of mitochondrial membrane potential, and respiration, apy (for example, sorafenib) [121]. Although it was initially
while ferroptosis inhibitors, such as DFO, ferrostatin-1, and suggested that ferroptosis was responsible for acetamino-
liproxstatin-1, but also CRISPR/Cas9 Bid knockout and the phen- (APAP; paracetamol) induced liver injury [122, 123],
BID inhibitor BI-6c9, protected against RSL3 toxicity. They recently published papers argue against this hypothesis
presented new data that the mitochondria-targeted ROS scav- [124, 125]. Jaescke et al. [125] critically reviewed this issue
and suggested that there is no evidence for a quantitatively islets isolated for transplantation are susceptible to erastin-
sufficient amount of lipid peroxides to cause cell death, and and RSL3-induced ferroptosis and that this can be sup-
thus, APAP hepatotoxicity is not caused by ferroptosis. At pressed by ferrostatin-1.
the same time, the authors did not exclude the significance With such a background as the starting point, the exam-
of mitochondrial oxidative stress (peroxynitrate) in APAP- ination of ferroptosis in diabetic conditions represents an
induced hepatotoxicity. intriguing and important scientific field that holds great
Mitochondrial dysfunction plays a critical role in potential for the improvement of antidiabetic therapy. Our
the pathogenesis of different liver and kidney diseases efforts along these lines are in progress.
[126, 127], but it is usually linked with tissue injury
due to apoptosis, rarely ferroptosis. One of these rare exam- 9. Mitochondria-Specific Strategies and Future
ples comes from studies of an in vitro model of kidney I/R Directions in Targeting Ferroptosis
injury that showed that erastin-induced ferroptosis in human
kidney-2 (HK-2) cell lines was mediated by changes in mito- According to the presented information related to mitochon-
chondrial metabolism, such as hyperpolarization of the mito- dria and ferroptosis reviewed herein, the targeting of mito-
chondrial membrane [128] or interaction with a specific chondrial metabolism presents a new concept for effective
mitochondrially localized protein ALR (augmenter of lipid (i) antiferroptotic (cardiovascular and neurodegenerative
regeneration) [129]. Acute renal failure induced by GPX4 diseases) and (ii) proferroptotic (cancer) strategies.
inactivation is accompanied by the accumulation of oxidized Considering the studies summarized in the present
cardiolipin in mitochondria and consequent ferroptosis [19]. review, an antiferroptotic strategy that deserves more
Scarce data on the role of mitochondria in liver and kid- attention could be the use of specific mitochondria-targeted
ney disease-related ferroptosis, along with the significant antioxidants. The requirement for organelle-targeted antiox-
impact of this process on their pathogenesis, has opened idants and even more targeting of the specific site of ROS
the field for further examination, with the final aim of produc- production [76] has emerged after the failure of most antiox-
ing novel mitochondria-targeted antiferroptotic approaches idant therapies to achieve significant outcomes in clinical
for the treatment of different pathologies. trials [141, 142]. A possible reason for this is that after
in vivo application, only a small amount of antioxidant
8. Ferroptosis in Metabolic Disorders: Possible reaches cellular organelles, including the mitochondria.
Implication in Diabetes Thus, great effort has been invested in the design and testing
of mitochondria-targeted antioxidants in a wide range of
In addition to the previously mentioned diseases, mitochon- pathological conditions where mitochondrial dysfunction
drial dysfunction plays an important role in the pathogenesis followed by increased mitochondrial ROS production has a
of metabolic disorders, such as obesity, metabolic syndrome, significant impact [143–147].
and diabetes. The involvement of cell death (apoptosis, To date, several mitochondria-targeted antioxidants have
necrosis, and autophagy) in diabetes and its link with mito- shown promise in the treatment of human pathologies such
chondrial dysfunction are well documented [117, 130, 131]. as neurodegenerative diseases [148], ischemia/reperfusion
To date, there are no studies confirming the role of ferropto- [149, 150], diabetes [151–153], hypertension [154, 155],
sis in the regulation of β-cell mass and the pathology of and renal diseases [156, 157]. This list includes MitoVitE,
tissues in the diabetic state. However, there are several pecu- MitoQ, MitoTEMPO(L), and MitoLipoic acid. The beneficial
liarities that characterize the diabetic phenotype, and the effects of such compounds are commonly seen as a decrease
pancreas itself, that speak in favour of the possible involve- in oxidative stress in the mitochondria and consequent
ment of ferroptosis in the aetiology and pathogenesis of this improvement in the pathologies, reflected through specific
disease. parameters including tissue damage and cell death. In this
First, the production of ROS is increased in the diabetic context, apoptosis, as a form of mitochondria-related cell
state, especially at the mitochondrial level, due to (i) hyper- death, is well studied, and the expected benefit of targeted anti-
glycaemia, (ii) hyperlipidaemia, (iii) hyperinsulinemia, and oxidants has been confirmed in many cases [154, 158, 159].
(iv) iron overload [132–135]. Along with the increase in the Judging by the growing evidence for the involvement of
production of ROS, the antioxidative defence is decreased mitochondrial ROS accumulation in ferroptosis in different
in many diabetes-targeted tissues [136, 137]. This leads to pathological states as reviewed here, we believe that the use
an increase in oxidative pressure commonly seen as an of antioxidants that specifically target these organelles has
increase in the level of lipid peroxidation end products, sug- promising potential as an antiferroptotic strategy in many
gesting that the GPX4-GSH antioxidant axis is compromised pathologies. To date, there are only a few studies that deal
in this condition [138, 139]. Along with this, β-cells are with the effects of mitochondria-targeted antioxidants on fer-
extremely sensitive to oxidative insults due to the intrinsically roptosis and ferroptosis-related events. In most of these stud-
low expression and activity of antioxidative enzymes, includ- ies, these antioxidants have been used as tools for examining
ing GPX [140]. In line with the hypothesis that β-cells are the contribution of mitochondria to the process of ferroptosis
prone to ferroptosis, the recent paper from Bruni et al. [68] per se [30, 35, 36], while in some recently published papers,
argues that the viability and function of pancreatic β-islets their protective effects in several pathological conditions have
in vitro are highly compromised in the presence of been ascribed to the suppression of ferroptosis [33, 160].
ferroptosis-inducing agents. The authors showed that human Importantly, these data have paved the way for future
research directed at the development of antiferroptotic strat- aetiology of all the above-mentioned diseases and that mito-
egies in many pathological conditions. chondrial pathways are likely involved in the regulation of
In addition to mitochondria-targeted antioxidants, ferroptosis. Therefore, mitochondria and mitochondria-
mitochondria-permeable iron chelators could be a promising related signalling are promising targets for modulating fer-
approach for the suppression of mitochondrial iron overload roptosis and warrant further examination with the aim of
and the consequent process of ferroptosis. DFO has com- obtaining improved understanding and treatment of these
monly been used for testing the sensitivity of ferroptosis- pathologies. We have specifically highlighted here the issues
related events in the modulation of intracellular iron. DFO that should be addressed in future research and that may
is not very membrane-permeable and cannot effectively eventually be considered potential targets in pro-/antiferrop-
chelate intracellular iron in some tissues such as the heart totic therapy of the mentioned diseases, as well as in other
[161, 162] and brain [163]. Although Dixon et al. [12] pathological conditions accompanied by increased cell death
showed in the first study defining ferroptosis that and/or impaired mitochondrial function.
membrane-permeable iron chelators such as 2,2-bipyridyl
(2,2-BP) provide adequate protection against ferroptotic cell
death, such that modulators of iron concentrations have not Data Availability
been sufficiently exploited in subsequent studies of this type No data were used to support this study.
of cell death. We believe that these avenues for targeting fer-
roptosis require attention as a therapeutic strategy in many
pathologies where iron overload in the mitochondria plays Conflicts of Interest
a significant role, at least in neurodegenerative diseases and
cardiomyopathies [164, 165]. The authors have no conflicts of interest to declare.
In the context of cancer therapy, an opposite approach
should be applied, one that is directed to the induction of fer- Authors’ Contributions
roptosis by targeting mitochondria. A constant aim in cancer
therapy is to overcome resistance to cell death in cancer cells V.O. and A.S. conceptualized and drafted the paper. M.V.
due to their specific mitochondrial phenotypes [166]. Multi- critically revised and edited the manuscript. I.G. and V.M.
ple strategies have been developed thus far, including those critically revised the manuscript.
that target the ETC and OXPHOS functions, glycolysis, the
TCA cycle, ROS homeostasis, and permeability transition
pores [167, 168]. The antitumour activity of many of them
Acknowledgments
interferes with the pathways that lead to increased ROS pro- This work was supported by the Ministry of Education,
duction, and they can induce apoptosis with varying success. Science and Technological Development of the Republic of
Given the versatile roles of mitochondria in cancer cells, Serbia (Contract No. 451-03-68/2020-14/200007) and by
more mitochondria-based therapies are warranted. In this the Science Fund of the Republic of Serbia (Serbian Science
context, proferroptotic mitochondria-related cancer therapy and Diaspora Collaboration Program: Knowledge Exchange
promises to overcome the drawbacks of traditional therapies Vouchers, #Grant No. 6525651, Ferroptosis in the β-cells
mediated by apoptosis and should be extensively studied in death: possible strategy for diabetes treatment, acronym:
the future. Among the proferroptotic agents, erastin has been BetFeSis), and this review is prepared as a starting point
the most extensively studied as an anticancer agent. It acts by research for this project.
opening the VDAC and the consequent increase in mito-
chondrial ROS production followed by ferroptotic-related
events [169]. References
Thus, we suggest that the commonly used mitochondria-
directed approaches should now be exploited in a completely [1] https://www.who.int/news-room/fact-sheets/detail/the-top-
10-causes-of-death.
new context which is focused on the process of ferroptosis.
[2] S. A. Susin, H. K. Lorenzo, N. Zamzami et al., “Molecular
This could be a promising strategy in overcoming major
characterization of mitochondrial apoptosis-inducing fac-
problems in the pathologies mentioned in the present review tor,” Nature, vol. 397, no. 6718, pp. 441–446, 1999.
and dysregulation of cell death signalling pathways and in
[3] M. R. Duchen, “Mitochondria and calcium: from cell signal-
improving existing therapies. ling to cell death,” The Journal of Physiology, vol. 529, no. 1,
pp. 57–68, 2000.
10. Conclusion [4] L. D. Osellame, T. S. Blacker, and M. R. Duchen, “Cellular
and molecular mechanisms of mitochondrial function,” Best
With the highest mortality rates worldwide, cancer, neurode- Practice & Research Clinical Endocrinology & Metabolism,
generative, cardiovascular, and hematologic diseases, and vol. 26, no. 6, pp. 711–723, 2012.
ischemia/reperfusion injury of the heart, brain, and kidney [5] S. Javadov, A. V. Kozlov, and A. K. S. Camara, “Mitochondria
occupy the attention of scientists searching for effective novel in health and diseases,” Cells, vol. 9, no. 5, p. 1177, 2020.
approaches for treating these high-impact pathologies. [6] P. D. Bhola and A. Letai, “Mitochondria–Judges and Execu-
Extensive research that has been performed during the last tioners of Cell Death Sentences,” Molecular Cell, vol. 61,
years indicates that ferroptosis might be involved in the no. 5, pp. 695–704, 2016.
[7] C. B. Thompson, “Apoptosis in the pathogenesis and treat- redox biology, and disease,” Cell, vol. 171, no. 2, pp. 273–
ment of disease,” Science, vol. 267, no. 5203, pp. 1456–1462, 285, 2017.
1995. [25] S. Neitemeier, A. Jelinek, V. Laino et al., “BID links ferropto-
[8] N. Singh, “Apoptosis in health and disease and modulation of sis to mitochondrial cell death pathways,” Redox Biology,
apoptosis for therapy: an overview,” Indian Journal of Clini- vol. 12, pp. 558–570, 2017.
cal Biochemistry, vol. 22, no. 2, pp. 6–16, 2007. [26] H. Wang, C. Liu, Y. Zhao, and G. Gao, “Mitochondria regu-
[9] F. X. Sureda, F. Junyent, E. Verdaguer et al., “Antiapoptotic lation in ferroptosis,” European Journal of Cell Biology,
drugs: a therapautic strategy for the prevention of neuro- vol. 99, no. 1, article 151058, 2020.
degenerative diseases,” Current Pharmaceutical Design, [27] M. Gao, J. Yi, J. Zhu et al., “Role of mitochondria in ferropto-
vol. 17, no. 3, pp. 230–245, 2011. sis,” Molecular Cell, vol. 73, no. 2, pp. 354–363.e3, 2019.
[10] K. Konstantinidis, R. S. Whelan, and R. N. Kitsis, “Mecha- [28] T. Krainz, M. M. Gaschler, C. Lim, J. R. Sacher, B. R. Stock-
nisms of cell death in heart disease,” Arteriosclerosis, Throm- well, and P. Wipf, “A mitochondrial targeted nitroxide is a
bosis, and Vascular Biology, vol. 32, no. 7, pp. 1552–1562, potent inhibitor of ferroptosis,” ACS Central Science, vol. 2,
2012. no. 9, pp. 653–659, 2016.
[11] A. B. Carneiro and W. S. el-Deiry, “Targeting apoptosis in [29] M. M. Gaschler, F. Hu, H. Feng, A. Linkermann, W. Min, and
cancer therapy,” Nature Reviews Clinical Oncology, vol. 17, B. R. Stockwell, “Determination of the subcellular localization
no. 7, pp. 395–417, 2020. and mechanism of action of ferrostatins in suppressing fer-
[12] S. J. Dixon, K. M. Lemberg, M. R. Lamprecht et al., “Ferrop- roptosis,” ACS Chemical Biology, vol. 13, no. 4, pp. 1013–
tosis: an iron-dependent form of nonapoptotic cell death,” 1020, 2018.
Cell, vol. 149, no. 5, pp. 1060–1072, 2012. [30] T. Homma, S. Kobayashi, H. Sato, and J. Fujii, “Superoxide
[13] Y. Xie, W. Hou, X. Song et al., “Ferroptosis: process and func- produced by mitochondrial complex III plays a pivotal role
tion,” Cell Death & Differentiation, vol. 23, no. 3, pp. 369– in the execution of ferroptosis induced by cysteine starva-
379, 2016. tion,” Archives of Biochemistry and Biophysics, vol. 700, arti-
[14] S. Doll, B. Proneth, Y. Y. Tyurina et al., “ACSL4 dictates fer- cle 108775, 2021.
roptosis sensitivity by shaping cellular lipid composition,” [31] Y. Feng, N. B. Madungwe, A. D. Imam Aliagan, N. Tombo,
Nature Chemical Biology, vol. 13, no. 1, pp. 91–98, 2017. and J. C. Bopassa, “Liproxstatin-1 protects the mouse myo-
[15] B. S. P. Shirlee Tan, B. S. P. David Schubert, and B. S. P. cardium against ischemia/reperfusion injury by decreasing
Pamela Maher, “Oxytosis: a novel form of programmed cell VDAC1 levels and restoring GPX4 levels,” Biochemical and
death,” Current Topics in Medicinal Chemistry, vol. 1, no. 6, Biophysical Research Communications, vol. 520, no. 3,
pp. 497–506, 2001. pp. 606–611, 2019.
[16] J. Lewerenz, G. Ates, A. Methner, M. Conrad, and P. Maher, [32] Y. Q. Wang, S. Y. Chang, Q. Wu et al., “The protective role of
“Oxytosis/ferroptosis-(Re-) emerging roles for oxidative mitochondrial ferritin on erastin-induced ferroptosis,” Fron-
stress-dependent non-apoptotic cell death in diseases of the tiers in Aging Neuroscience, vol. 8, p. 308, 2016.
central nervous system,” Frontiers in Neuroscience, vol. 20, [33] X. X. Fang, H. Wang, D. Han et al., “Ferroptosis as a target for
no. 12, p. 214, 2018. protection against cardiomyopathy,” Proceedings of the
[17] P. Maher, A. Currais, and D. Schubert, “Using the oxytosis/ National Academy of Sciences of the United States of America,
ferroptosis pathway to understand and treat age-associated vol. 116, no. 7, pp. 2672–2680, 2019.
neurodegenerative diseases,” Cell Chemical Biology, vol. 27, [34] M. G. Cotticelli, S. Xia, D. Lin et al., “Ferroptosis as a novel
no. 12, pp. 1456–1471, 2020. therapeutic target for Friedreich's ataxia,” Journal of Pharma-
[18] A. Linkermann, R. Skouta, N. Himmerkus et al., “Synchro- cology and Experimental Therapeutics, vol. 369, no. 1, pp. 47–
nized renal tubular cell death involves ferroptosis,” Proceed- 54, 2019.
ings of the National Academy of Sciences of the United States [35] A. Jelinek, L. Heyder, M. Daude et al., “Mitochondrial
of America, vol. 111, no. 47, pp. 16836–16841, 2014. rescue prevents glutathione peroxidase-dependent ferrop-
[19] J. P. Friedmann Angeli, M. Schneider, B. Proneth et al., “Inac- tosis,” Free Radical Biology & Medicine, vol. 117,
tivation of the ferroptosis regulator Gpx4 triggers acute renal pp. 45–57, 2018.
failure in mice,” Nature Cell Biology, vol. 16, no. 12, pp. 1180– [36] D. N. DeHart, D. Fang, K. Heslop, L. Li, J. J. Lemasters, and
1191, 2014. E. N. Maldonado, “Opening of voltage dependent anion
[20] M. Gao, P. Monian, N. Quadri, R. Ramasamy, and X. Jiang, channels promotes reactive oxygen species generation, mito-
“Glutaminolysis and transferrin regulate ferroptosis,” Molec- chondrial dysfunction and cell death in cancer cells,” Bio-
ular Cell, vol. 59, no. 2, pp. 298–308, 2015. chemical Pharmacology, vol. 148, pp. 155–162, 2018.
[21] G. Gao and Y. Z. Chang, “Mitochondrial ferritin in the regu- [37] N. Yagoda, M. von Rechenberg, E. Zaganjor et al., “RAS-
lation of brain iron homeostasis and neurodegenerative dis- RAF-MEK-dependent oxidative cell death involving
eases,” Frontiers in Pharmacology, vol. 5, p. 19, 2014. voltage-dependent anion channels,” Nature, vol. 447,
[22] A. Anandhan, M. Dodson, C. J. Schmidlin, P. Liu, and D. D. no. 7146, pp. 864–868, 2007.
Zhang, “Breakdown of an ironclad defense system: the critical [38] R. Justo, M. Frontera, E. Pujol et al., “Gender-related differ-
role of NRF2 in mediating ferroptosis,” Cell Chemical Biology, ences in morphology and thermogenic capacity of brown adi-
vol. 27, no. 4, pp. 436–447, 2020. pose tissue mitochondrial subpopulations,” Life Sciences,
[23] J. Li, F. Cao, H. L. Yin et al., “Ferroptosis: past, present and vol. 76, no. 10, pp. 1147–1158, 2005.
future,” Cell Death & Disease, vol. 11, no. 2, p. 88, 2020. [39] V. Petrović, A. Korać, B. Buzadzić et al., “Nitric oxide regu-
[24] B. R. Stockwell, J. P. Friedmann Angeli, H. Bayir et al., “Fer- lates mitochondrial re-modelling in interscapular brown adi-
roptosis: a regulated cell death nexus linking metabolism, pose tissue: ultrastructural and morphometric-stereologic
studies,” Journal of Microscopy, vol. 232, no. 3, pp. 542–548, [55] W. S. Yang, R. SriRamaratnam, M. E. Welsch et al., “Regula-
2008. tion of ferroptotic cancer cell death by GPX4,” Cell, vol. 156,
[40] V. Petrović, B. Buzadzić, A. Korać, A. Vasilijević, A. Janković, no. 1-2, pp. 317–331, 2014.
and B. Korać, “NO modulates the molecular basis of rat inter- [56] Y. Li, P. Maher, and D. Schubert, “A role for 12-lipoxygenase
scapular brown adipose tissue thermogenesis,” Comparative in nerve cell death caused by glutathione depletion,” Neuron,
Biochemistry and Physiology Part C: Toxicology & Pharma- vol. 19, no. 2, pp. 453–463, 1997.
cology, vol. 152, no. 2, pp. 147–159, 2010. [57] R. C. Hider and X. L. Kong, “Glutathione: a key component of
[41] B. Halliwell, “Reactive species and antioxidants. Redox biol- the cytoplasmic labile iron pool,” BioMetals, vol. 24, no. 6,
ogy is a fundamental theme of aerobic life,” Plant Physiology, pp. 1179–1187, 2011.
vol. 141, no. 2, pp. 312–322, 2006. [58] J. D. Hayes, J. U. Flanagan, and I. R. Jowsey, “Glutathione
[42] N. A. Porter, “Mechanisms for the autoxidation of polyunsat- transferases,” Annual Review of Pharmacology and Toxicol-
urated lipids,” Accounts of Chemical Research, vol. 19, no. 9, ogy, vol. 45, no. 1, pp. 51–88, 2005.
pp. 262–268, 1986. [59] S. J. Dixon, D. N. Patel, M. Welsch et al., “Pharmacological
[43] H. Feng and B. R. Stockwell, “Unsolved mysteries: how does inhibition of cystine-glutamate exchange induces endoplas-
lipid peroxidation cause ferroptosis?,” PLOS Biology, vol. 16, mic reticulum stress and ferroptosis,” eLife, vol. 3, article
no. 5, article e2006203, 2018. e02523, 2014.
[44] P. Lei, T. Bai, and Y. Sun, “Mechanisms of ferroptosis and [60] S. Dolma, S. L. Lessnick, W. C. Hahn, and B. R. Stockwell,
relations with regulated cell death: a review,” Frontiers in “Identification of genotype-selective antitumor agents using
Physiology, vol. 10, p. 139, 2019. synthetic lethal chemical screening in engineered human
[45] D. A. Stoyanovsky, Y. Y. Tyurina, I. Shrivastava et al., “Iron tumor cells,” Cancer Cell, vol. 3, no. 3, pp. 285–296, 2003.
catalysis of lipid peroxidation in ferroptosis: regulated enzy- [61] J. B. Davis and P. Maher, “Protein kinase C activation inhibits
matic or random free radical reaction?,” Free Radical Biology glutamate-induced cytotoxicity in a neuronal cell line,” Brain
& Medicine, vol. 133, pp. 153–161, 2019. Research, vol. 652, no. 1, pp. 169–173, 1994.
[46] A. Catalá and M. Díaz, “Editorial: impact of lipid peroxida- [62] T. H. Murphy, M. Miyamoto, A. Sastre, R. L. Schnaar, and
tion on the physiology and pathophysiology of cell mem- J. T. Coyle, “Glutamate toxicity in a neuronal cell line
branes,” Frontiers in Physiology, vol. 7, p. 423, 2016. involves inhibition of cystine transport leading to oxidative
[47] C. T. Heffern, L. Pocivavsek, A. A. Birukova et al., “Thermo- stress,” Neuron, vol. 2, no. 6, pp. 1547–1558, 1989.
dynamic and kinetic investigations of the release of oxidized [63] R. Skouta, S. J. Dixon, J. Wang et al., “Ferrostatins inhibit oxi-
phospholipids from lipid membranes and its effect on vascu- dative lipid damage and cell death in diverse disease models,”
lar integrity,” Chemistry and Physics of Lipids, vol. 175-176, Journal of the American Chemical Society, vol. 136, no. 12,
pp. 9–19, 2013. pp. 4551–4556, 2014.
[48] J. Wong-Ekkabut, Z. Xu, W. Triampo, I. M. Tang, D. P. Tiele- [64] Y. Kang, S. Tiziani, G. Park, M. Kaul, and G. Paternostro,
man, and L. Monticelli, “Effect of lipid peroxidation on the “Cellular protection using Flt3 and PI3Kα inhibitors demon-
properties of lipid bilayers: a molecular dynamics study,” Bio- strates multiple mechanisms of oxidative glutamate toxicity,”
physical Journal, vol. 93, no. 12, pp. 4225–4236, 2007. Nature Communications, vol. 5, no. 1, p. 3672, 2014.
[49] J. W. Borst, N. V. Visser, O. Kouptsova, and A. J. Visser, [65] A. M. Battaglia, R. Chirillo, I. Aversa, A. Sacco, F. Costanzo,
“Oxidation of unsaturated phospholipids in membrane and F. Biamonte, “Ferroptosis and cancer: mitochondria
bilayer mixtures is accompanied by membrane fluidity meet the “iron maiden” cell death,” Cells, vol. 9, no. 6,
changes,” Biochimica et Biophysica Acta (BBA) - Molecular p. 1505, 2020.
and Cell Biology of Lipids, vol. 1487, no. 1, pp. 61–73, 2000. [66] S. Torii, R. Shintoku, C. Kubota et al., “An essential role for
[50] S. Dalleau, M. Baradat, F. Gueraud, and L. Huc, “Cell death functional lysosomes in ferroptosis of cancer cells,” Biochem-
and diseases related to oxidative stress:4-hydroxynonenal ical Journal, vol. 473, no. 6, pp. 769–777, 2016.
(HNE) in the balance,” Cell Death & Differentiation, vol. 20, [67] Y. Shen, X. Li, D. Dong, B. Zhang, Y. Xue, and P. Shang,
no. 12, pp. 1615–1630, 2013. “Transferrin receptor 1 in cancer: a new sight for cancer ther-
[51] P. Chaudhary, R. Sharma, A. Sharma et al., “Mechanisms apy,” American Journal of Cancer Research, vol. 8, no. 6,
of 4-hydroxy-2-nonenal induced pro- and anti-apoptotic pp. 916–931, 2018.
signaling,” Biochemistry, vol. 49, no. 29, pp. 6263–6275, [68] A. Bruni, A. R. Pepper, R. L. Pawlick et al., “Ferroptosis-
2010. inducing agents compromise in vitro human islet viability
[52] A. Ayala, M. F. Muñoz, and S. Argüelles, “Lipid peroxidation: and function,” Cell Death & Disease, vol. 9, no. 6, p. 595,
production, metabolism, and signaling mechanisms of mal- 2018.
ondialdehyde and 4-hydroxy-2-nonenal,” Oxidative Medi- [69] M. Dodson, R. Castro-Portuguez, and D. D. Zhang,
cine and Cellular Longevity, vol. 2014, Article ID 360438, 31 “NRF2 plays a critical role in mitigating lipid peroxida-
pages, 2014. tion and ferroptosis,” Redox Biology, vol. 23, article 101107,
[53] Y. Zou, H. Li, E. T. Graham et al., “Cytochrome P450 oxido- 2019.
reductase contributes to phospholipid peroxidation in fer- [70] B. Daher, M. Vučetić, and J. Pouysségur, “Cysteine depletion,
roptosis,” Nature Chemical Biology, vol. 16, no. 3, pp. 302– a key action to challenge cancer cells to ferroptotic cell death,”
309, 2020. Frontiers in Oncology, vol. 10, p. 723, 2020.
[54] Y. Chen, Y. Liu, T. Lan et al., “Quantitative profiling of pro- [71] E. Agmon, J. Solon, P. Bassereau, and B. R. Stockwell,
tein carbonylations in ferroptosis by an aniline-derived “Modeling the effects of lipid peroxidation during ferroptosis
probe,” Journal of the American Chemical Society, vol. 140, on membrane properties,” Scientific Reports, vol. 8, no. 1,
no. 13, pp. 4712–4720, 2018. p. 5155, 2018.
[72] C. Louandre, Z. Ezzoukhry, C. Godin et al., “Iron-dependent peroxidase pathway,” Nature, vol. 547, no. 7664, pp. 453–
cell death of hepatocellular carcinoma cells exposed to soraf- 457, 2017.
enib,” International Journal of Cancer, vol. 133, no. 7, [89] M. D. Arensman, X. S. Yang, D. M. Leahy et al., “Cystine–glu-
pp. 1732–1742, 2013. tamate antiporter xCT deficiency suppresses tumor growth
[73] Z. Wang, M. Wang, and B. I. Carr, “Involvement of receptor while preserving antitumor immunity,” Proceedings of the
tyrosine phosphatase DEP-1 mediated PI3K-cofilin signaling National Academy of Sciences of the United States of America,
pathway in sorafenib-induced cytoskeletal rearrangement in vol. 116, no. 19, pp. 9533–9542, 2019.
hepatoma cells,” Journal of Cellular Physiology, vol. 224, [90] T. Ishikawa, Y. Kajimoto, Y. Inoue, Y. Ikegami, and
no. 2, pp. 559–565, 2010. T. Kuroiwa, “Critical role of ABCG2 in ALA-photodynamic
[74] D. R. Wise and C. B. Thompson, “Glutamine addiction: a new diagnosis and therapy of human brain tumor,” Advances in
therapeutic target in cancer,” Trends in Biochemical Sciences, Cancer Research, vol. 125, pp. 197–216, 2015.
vol. 35, no. 8, pp. 427–433, 2010. [91] M. Buccarelli, M. Marconi, S. Pacioni et al., “Inhibition of
[75] S. A. Novgorodov, J. R. Voltin, M. A. Gooz, L. Li, J. J. autophagy increases susceptibility of glioblastoma stem cells
Lemasters, and T. I. Gudz, “Acid sphingomyelinase promotes to temozolomide by igniting ferroptosis,” Cell Death & Dis-
mitochondrial dysfunction due to glutamate- induced regu- ease, vol. 9, no. 8, p. 841, 2018.
lated necrosis,” Journal of Lipid Research, vol. 59, no. 2, [92] P. E. Porporato, N. Filigheddu, J. M. B.-S. Pedro, G. Kroemer,
pp. 312–329, 2018. and L. Galluzzi, “Mitochondrial metabolism and cancer,” Cell
[76] Y. Liu and D. R. Schubert, “The specificity of neuroprotection Researh, vol. 28, pp. 265–280, 2017.
by antioxidants,” Journal of Biomedical Science, vol. 16, no. 1, [93] N. Badrinath and S. Y. Yoo, “Mitochondria in cancer: in the
p. 98, 2009. aspects of tumorigenesis and targeted therapy,” Carcinogene-
[77] D. Voet and J. G. Voet, Biochemistry, J. Wiley & Sons, New sis, vol. 39, no. 12, pp. 1419–1430, 2018.
York, NY, USA, 1995. [94] S. W. Tait, A. Oberst, G. Quarato et al., “Widespread mito-
[78] A. J. Case, S. Li, U. Basu, J. Tian, and M. C. Zimmerman, chondrial depletion via mitophagy does not compromise
“Mitochondrial-localized NADPH oxidase 4 is a source of necroptosis,” Cell Reports, vol. 5, no. 4, pp. 878–885, 2013.
superoxide in angiotensin II-stimulated neurons,” American [95] F. Ye, W. Chai, M. Xie et al., “HMGB1 regulates erastin-
Journal of Physiology-Heart and Circulatory Physiology, induced ferroptosis via RAS-JNK/p38 signaling in HL-
vol. 305, no. 1, pp. H19–H28, 2013. 60/NRASQ61L cells,” American Journal of Cancer Research,
[79] V. Adam-Vizi and L. Tretter, “The role of mitochondrial vol. 9, no. 4, pp. 730–739, 2019.
dehydrogenases in the generation of oxidative stress,” Neu- [96] P. Schroeder, T. Gremmel, M. Berneburg, and J. Krutmann,
rochemistry International, vol. 62, no. 5, pp. 757–763, “Partial depletion of mitochondrial DNA from human skin
2013. fibroblasts induces a gene expression profile reminiscent of
[80] V. Shoshan-Barmatz, D. P. Vito, M. Zweckstetter, Z. Raviv, photoaged skin,” Journal of Investigative Dermatology,
N. Keinan, and N. Arbel, “VDAC, a multi-functional mito- vol. 128, no. 9, pp. 2297–2303, 2008.
chondrial protein regulating cell life and death,” Molecular [97] K. Tomita, Y. Takashi, Y. Ouchi et al., “Lipid peroxidation
Aspects of Medicine, vol. 31, no. 3, pp. 227–285, 2010. increases hydrogen peroxide permeability leading to cell
[81] W. S. Yang and B. R. Stockwell, “Synthetic lethal screening death in cancer cell lines that lack mtDNA,” Cancer Science,
identifies compounds activating iron-dependent, nonapopto- vol. 110, no. 9, pp. 2856–2866, 2019.
tic cell death in oncogenic-RAS-harboring cancer cells,” [98] Y. Takashi, K. Tomita, Y. Kuwahara et al., “Mitochondrial
Chemistry & Biology, vol. 15, no. 3, pp. 234–245, 2008. dysfunction promotes aquaporin expression that controls
[82] B. Do van, F. Gouel, A. Jonneaux et al., “Ferroptosis, a newly hydrogen peroxide permeability and ferroptosis,” Free Radi-
characterized form of cell death in Parkinson's disease that is cal Biology &s Medicine, vol. 161, pp. 60–70, 2020.
regulated by PKC,” Neurobiology of Disease, vol. 94, pp. 169– [99] M. Ždralević, M. Vučetić, B. Daher, I. Marchiq, S. K. Parks,
178, 2016. and J. Pouysségur, “Disrupting the 'Warburg effect' re-
[83] S. Alvarez, V. Sviderskiy, E. Terzi et al., “NFS1 undergoes routes cancer cells to OXPHOS offering a vulnerability point
positive selection in lung tumours and protects cells from fer- via 'ferroptosis'-induced cell death,” Advances in Biological
roptosis,” Nature, vol. 551, no. 7682, pp. 639–643, 2017. Regulation, vol. 68, pp. 55–63, 2018.
[84] K. Bersuker, J. Hendricks, Z. Li et al., “The CoQ oxidoreduc- [100] D. F. Goldspink, J. G. Burniston, and L. B. Tan, “Cardiomyo-
tase FSP1 acts parallel to GPX4 to inhibit ferroptosis,” cyte death and the ageing and failing heart,” Experimental
Nature, vol. 575, no. 7784, pp. 688–692, 2019. Physiology, vol. 88, no. 3, pp. 447–458, 2003.
[85] T. Tadokoro, M. Ikeda, T. Ide et al., “Mitochondria-depen- [101] V. Vanempel, A. Bertrand, L. Hofstra, H. Crijns,
dent ferroptosis plays a pivotal role in doxorubicin cardio- P. Doevendans, and L. Dewindt, “Myocyte apoptosis in heart
toxicity,” JCI Insight, vol. 5, no. 9, article e132747, 2020. failure,” Cardiovascular Research, vol. 67, no. 1, pp. 21–29,
[86] H. Imai and Y. Nakagawa, “Biological significance of phos- 2005.
pholipid hydroperoxide glutathione peroxidase (PHGPx, [102] Y. Baba, J. K. Higa, B. K. Shimada et al., “Protective effects of
GPx4) in mammalian cells,” Free Radical Biology& Medicine, the mechanistic target of rapamycin against excess iron and
vol. 34, no. 2, pp. 145–169, 2003. ferroptosis in cardiomyocytes,” American Journal of
[87] M. J. Hangauer, V. S. Viswanathan, M. J. Ryan et al., “Drug- Physiology-Heart and Circulatory Physiology, vol. 314, no. 3,
tolerant persister cancer cells are vulnerable to GPX4 inhibi- pp. H659–H668, 2018.
tion,” Nature, vol. 551, no. 7679, pp. 247–250, 2017. [103] M. Jovic, A. Stancic, D. Nenadic et al., “Mitochondrial
[88] V. S. Viswanathan, M. J. Ryan, H. D. Dhruv et al., “Depen- molecular basis of sevoflurane and propofol cardioprotection
dency of a therapy-resistant state of cancer cells on a lipid in patients undergoing aortic valve replacement with
cardiopulmonary bypass,” Cellular Physiology and Biochem- [120] H. Wang, P. An, E. Xie et al., “Characterization of ferroptosis
istry, vol. 29, no. 1-2, pp. 131–142, 2012. in murine models of hemochromatosis,” Hepatology, vol. 66,
[104] M. Corral-Debrinski, T. Horton, M. T. Lott, J. M. Shoffner, no. 2, pp. 449–465, 2017.
M. Flint Beal, and D. C. Wallace, “Mitochondrial DNA dele- [121] X. Sun, Z. Ou, R. Chen et al., “Activation of the p62-Keap1-
tions in human brain: regional variability and increase with NRF2 pathway protects against ferroptosis in hepatocellular
advanced age,” Nature Genetics, vol. 2, no. 4, pp. 324–329, carcinoma cells,” Hepatology, vol. 63, no. 1, pp. 173–184,
1992. 2016.
[105] M. P. Chen, Z. I. Cabantchik, S. Chan, G. C. Chan, and Y. F. [122] T. Lőrincz, K. Jemnitz, T. Kardon, J. Mandl, and A. Szarka,
Cheung, “Iron overload and apoptosis of HL-1 cardiomyo- “Ferroptosis is involved in acetaminophen induced cell
cytes: effects of calcium channel blockade,” PLoS One, death,” Pathology & Oncology Research, vol. 21, no. 4,
vol. 23, article e112915, 2014. pp. 1115–1121, 2015.
[106] N. Sumneang, N. Siri-Angkul, S. Kumfu, S. Chattipakorn, [123] N. Yamada, T. Karasawa, H. Kimura et al., “Ferroptosis
and N. Chattipakorn, “The effects of iron overload on mito- driven by radical oxidation of n-6 polyunsaturated fatty acids
chondrial function, mitochondrial dynamics, and ferroptosis mediates acetaminophen-induced acute liver failure,” Cell
in cardiomyocytes,” Archives of Biochemistry and Biophysics, Death & Disease, vol. 11, no. 2, p. 144, 2020.
vol. 680, article 108241, 2020. [124] H. Jaeschke and A. Ramachandran, “Response to the opinion
[107] M. T. Lin and M. F. Beal, “Mitochondrial dysfunction and letter entitled role of ferroptosis in acetaminophen hepato-
oxidative stress in neurodegenerative diseases,” Nature, toxicity by Yamada et al.,” Archives of Toxicology, vol. 94,
vol. 443, no. 7113, pp. 787–795, 2006. no. 5, pp. 1771-1772, 2020.
[108] M. Shichiri, “The role of lipid peroxidation in neurological [125] H. Jaeschke, O. B. Adelusi, and A. Ramachandran, “Ferropto-
disorders,” Journal of Clinical Biochemistry and Nutrition, sis and acetaminophen hepatotoxicity -are we going down
vol. 54, no. 3, pp. 151–160, 2014. another rabbit hole?,” Gene Expression, 2021.
[109] A. Sugiyama and J. Sun, “Immunochemical detection of lipid [126] A. Mansouri, C.-H. Gattolliat, and T. Asselah, “Mitochon-
hydroperoxide- and aldehyde-modified proteins in diseases,” drial dysfunction and signaling in chronic liver diseases,”
Subcellular Biochemistry, vol. 77, pp. 115–1125, 2014. Gastroenterology, vol. 155, no. 3, pp. 629–647, 2018.
[110] M. A. Bradley-Whitman and M. A. Lovell, “Biomarkers of [127] R. Che, Y. Yuan, S. Huang, and A. Zhang, “Mitochondrial
lipid peroxidation in Alzheimer disease (AD): an update,” dysfunction in the pathophysiology of renal diseases,” meri-
Archives of Toxicology, vol. 89, no. 7, pp. 1035–1044, 2015. can Journal of Physiology-Renal Physiology, vol. 306,
[111] J. Zhou, Y. Jin, Y. Lei et al., “Ferroptosis is regulated by mito- pp. 367–378, 2014.
chondria in neurodegenerative diseases,” Neurodegenerative [128] L. Su, X. Jiang, C. Yang et al., “Pannexin 1 mediates ferropto-
Diseases, vol. 20, no. 1, pp. 20–34, 2020. sis that contributes to renal ischemia/reperfusion injury,” J.
[112] C. Wu, W. Zhao, J. Yu, S. Li, L. Lin, and X. Chen, “Induction Biol. Chem., vol. 294, no. 50, pp. 19395–19404, 2019.
of ferroptosis and mitochondrial dysfunction by oxidative [129] L.-L. Huang, X.-H. Liao, H. Sun, X. Jiang, Q. Liu, and
stress in PC12 cells,” Scientific Reports, vol. 8, no. 1, p. 574, L. Zhang, “Augmenter of liver regeneration protects the kid-
2018. ney from ischaemia-reperfusion injury in ferroptosis,” Jour-
[113] W. S. Hambright, R. S. Fonseca, L. Chen, R. Na, and Q. Ran, nal of Cellular and Molecular Medicine, vol. 23, no. 6,
“Ablation of ferroptosis regulator glutathione peroxidase 4 in pp. 4153–4164, 2019.
forebrain neurons promotes cognitive impairment and neu- [130] M. Karaca, C. Magnan, and C. Kargar, “Masse fonctionnelle
rodegeneration,” Redox Biology, vol. 12, pp. 8–17, 2017. des cellules β : implication dans le diabete de type 2 et inter-
[114] Q. Tang, L. L. Bai, Z. Zou et al., “Ferroptosis is newly charac- vention therapeutique,” Diabetes & Metabolism, vol. 35,
terized form of neuronal cell death in response to arsenite no. 2, pp. 77–84, 2009.
exposure,” Neurotoxicology, vol. 67, pp. 27–36, 2018. [131] P. Marchetti and M. Masini, “Autophagy and the pancreatic
[115] C. L. Hu, M. Nydes, K. L. Shanley, I. E. Morales Pantoja, T. A. beta-cell in human type 2 diabetes,” Autophagy, vol. 5,
Howard, and O. A. Bizzozero, “Reduced expression of the fer- no. 7, pp. 1055-1056, 2009.
roptosis inhibitor glutathione peroxidase-4 in multiple scle- [132] R. P. Robertson, J. Harmon, P. O. Tran, Y. Tanaka, and
rosis and experimental autoimmune encephalomyelitis,” H. Takahashi, “Glucose toxicity in beta-cells: type 2 diabetes,
Journal of Neurochemistry, vol. 148, no. 3, pp. 426–439, 2019. good radicals gone bad, and the glutathione connection,”
[116] S. Đurašević, M. Stojković, L. Bogdanović et al., “The effects Diabetes, vol. 52, no. 3, pp. 581–587, 2003.
of meldonium on the renal acute ischemia/reperfusion injury [133] M. Elsner, W. Gehrmann, and S. Lenzen, “Peroxisome-gener-
in rats,” International Journal of Molecular Sciences, vol. 20, ated hydrogen peroxide as important mediator of lipotoxicity
no. 22, p. 5747, 2019. in insulin-producing cells,” Diabetes, vol. 60, no. 1, pp. 200–
[117] A. Petrović, D. Bogojević, A. Korać et al., “Oxidative stress- 208, 2011.
dependent contribution of HMGB1 to the interplay between [134] M. Markelic, K. Velickovic, I. Golic et al., “The origin of lipo-
apoptosis and autophagy in diabetic rat liver,” Journal of fuscin in brown adipocytes of hyperinsulinaemic rats: the role
Physiology and Biochemistry, vol. 73, no. 4, pp. 511–521, of lipid peroxidation and iron,” Histology & Histopathology,
2017. vol. 28, no. 4, pp. 493–503, 2013.
[118] A. Havasi and S. C. Borkan, “Apoptosis and acute kidney [135] J. M. Fernández-Real, D. McClain, and M. Manco,
injury,” Kidney International, vol. 80, pp. 29–40, 2001. “Mechanisms linking glucose homeostasis and iron
[119] M. E. Guicciardi and G. J. Gores, “Apoptosis: a mechanism of metabolism toward the onset and progression of type 2
acute and chronic liver injury,” Gut, vol. 54, no. 7, pp. 1024– diabetes,” Diabetes Care, vol. 38, no. 11, pp. 2169–2176,
1033, 2005. 2015.
[136] R. Singh, P. Bhardwaj, and P. Sharma, “Antioxidant and tox- of the New York Academy of Sciences, vol. 1201, no. 1,
icological evaluation of Cassia sopherain streptozotocin- pp. 96–103, 2010.
induced diabetic Wistar rats,” Pharmacognosy Research, [152] G. Mao, G. A. Kraus, I. Kim et al., “A mitochondria targeted
vol. 5, no. 4, pp. 225–232, 2013. vitamin E derivative decreases hepatic oxidative stress and
[137] A. M. T. Al-Nahdi, A. John, and H. Raza, “Cytoprotective inhibits fat deposition in mice,” The Journal of Nutrition,
effects of N-acetylcysteine on streptozotocin-induced oxida- vol. 140, no. 8, pp. 1425–1431, 2010.
tive stress and apoptosis in RIN-5F pancreatic β-cells,” Cellu- [153] R. Ni, T. Cao, S. Xiong et al., “Therapeutic inhibition of
lar Physiology and Biochemistry, vol. 51, no. 1, pp. 201–216, mitochondrial reactive oxygen species with mito- TEMPO
2018. reduces diabetic cardiomyopathy,” Free Radical Biology&
[138] Y. Ihara, S. Toyokuni, K. Uchida et al., “Hyperglycemia Medicine, vol. 90, pp. 12–23, 2016.
causes oxidative stress in pancreatic beta-cells of GK rats, a [154] D. Graham, N. N. Huynh, C. A. Hamilton et al., “Mitochon-
model of type 2 diabetes,” Diabetes, vol. 48, no. 4, pp. 927– dria-targeted antioxidant MitoQ10 improves endothelial
932, 1999. function and attenuates cardiac hypertrophy,” Hypertension,
[139] S. I. Gorogawa, Y. Kajimoto, Y. Umayahara et al., “Probucol vol. 54, no. 2, pp. 322–328, 2009.
preserves pancreatic β-cell function through reduction of [155] A. E. Dikalova, A. T. Bikineyeva, K. Budzyn et al., “Ther-
oxidative stress in type 2 diabetes,” Diabetes Research and apeutic targeting of mitochondrial superoxide in hyperten-
Clinical Practice, vol. 57, no. 1, pp. 1–10, 2002. sion,” Circulation Research, vol. 107, no. 1, pp. 106–116,
[140] S. Lenzen, “Oxidative stress: the vulnerable β-cell,” Biochem- 2010.
ical Society Transactions, vol. 36, no. 3, pp. 343–347, 2008. [156] Y. Ishimoto, R. Inagi, D. Yoshihara et al., “Mitochondrial
[141] G. Bjelakovic, D. Nikolova, L. L. Gluud, R. G. Simonetti, and abnormality facilitates cyst formation in autosomal dominant
C. Gluud, “Antioxidant supplements for prevention of mor- polycystic kidney disease,” Molecular and Cellular Biology,
tality in healthy participants and patients with various dis- vol. 37, no. 24, 2017.
eases,” Cochrane Database of Systematic Reviews, vol. 2, [157] C. I. Galarreta, M. S. Forbes, B. A. Thornhill et al., “The swan-
article CD007176, 2008. neck lesion: proximal tubular adaptation to oxidative stress in
[142] H. . M. Cochemé, C. Quin, S. . J. McQuaker et al., “Measure- nephropathic cystinosis,” American Journal of Physiology-
ment of H2O2 within Living _Drosophila_ during Aging Renal Physiology, vol. 308, pp. 1155–1166, 2015.
Using a Ratiometric Mass Spectrometry Probe Targeted to [158] W. Ding, T. Liu, X. Bi, and Z. Zhang, “Mitochondria-targeted
the Mitochondrial Matrix,” Cell Metabolism, vol. 13, no. 3, antioxidant Mito-Tempo protects against aldosterone-
pp. 340–350, 2011. induced renal injury in vivo,” Cellular Physiology and Bio-
[143] B. N. Ames, M. K. Shigenaga, and T. M. Hagen, “Oxidants, chemistry, vol. 44, no. 2, pp. 741–750, 2017.
antioxidants, and the degenerative diseases of aging,” Pro- [159] A. Dhanasekaran, S. Kotamraju, S. V. Kalivendi et al.,
ceedings of the National Academy of Sciences of the United “Supplementation of Endothelial Cells with Mitochondria-
States of America, vol. 90, pp. 7915–7922, 1993. targeted Antioxidants Inhibit Peroxide-induced Mitochon-
[144] K. B. Beckman and B. N. Ames, “The free radical theory of drial Iron Uptake, Oxidative Damage, and Apoptosis,” Jour-
aging matures,” Physiological Reviews, vol. 78, no. 2, nal of Biological Chemistry, vol. 279, no. 36, pp. 37575–
pp. 547–581, 1998. 37587, 2004.
[145] T. Finkel, “Radical medicine: treating ageing to cure disease,” [160] S. Wei, T. Qiu, X. Yao et al., “Arsenic induces pancreatic
Nature Reviews Molecular Cell Biology, vol. 6, no. 12, pp. 971– dysfunction and ferroptosis via mitochondrial ROS-
976, 2005. autophagy-lysosomal pathway,” Journal of Hazardous Mate-
[146] K. Green, M. D. Brand, and M. P. Murphy, “Prevention of rials, vol. 384, article 121390, 2020.
mitochondrial oxidative damage as a therapeutic strategy in [161] C. Hershko, “Oral iron chelators: new opportunities and new
diabetes,” Diabetes, vol. 53, Supplement 1, pp. S110–S118, dilemmas,” Haematologica, vol. 91, no. 10, pp. 1307–1312,
2004. 2006.
[147] H. H. Szeto, “Cell-permeable, mitochondrial-targeted, pep- [162] J. B. Porter, R. Rafique, S. Srichairatanakool et al., “Recent
tide antioxidants,” The AAPS Journal, vol. 8, no. 2, insights into interactions of deferoxamine with cellular and
pp. E277–E283, 2006. plasma iron pools: implications for clinical use,” Annals of
[148] M. J. McManus, M. P. Murphy, and J. L. Franklin, “The the New York Academy of Sciences, vol. 1054, no. 1,
mitochondria-targeted antioxidant MitoQ prevents loss of pp. 155–168, 2005.
spatial memory retention and early neuropathology in a [163] S. G. Lynch, T. Fonseca, and S. LeVine, “A multiple course
transgenic mouse model of Alzheimer’s disease,” Journal of trial of desferrioxamine in chronic progressive multiple scle-
Neuroscience, vol. 31, no. 44, pp. 15703–15715, 2011. rosis,” Cellular and Molecular Biology, vol. 46, no. 4, pp. 865–
[149] J. Neuzil, C. Widén, N. Gellert et al., “Mitochondria transmit 869, 2000.
apoptosis signalling in cardiomyocyte-like cells and isolated [164] N. P. Mena, P. J. Urrutia, F. Lourido, C. M. Carrasco, and
hearts exposed to experimental ischemia-reperfusion injury,” M. T. Núñez, “Mitochondrial iron homeostasis and its dys-
Redox Report, vol. 12, no. 3, pp. 148–162, 2007. functions in neurodegenerative disorders,” Mitochondrion,
[150] G. F. Kelso, A. Maroz, H. M. Cochemé et al., “A vol. 21, pp. 92–105, 2015.
Mitochondria-Targeted Macrocyclic Mn(II) Superoxide Dis- [165] R. Gordan, S. Wongjaikam, J. K. Gwathmey,
mutase Mimetic,” Chemistry & Biology, vol. 19, no. 10, N. Chattipakorn, S. C. Chattipakorn, and L.-H. Xie, “Involve-
pp. 1237–1246, 2012. ment of cytosolic and mitochondrial iron in iron overload
[151] R. A. J. Smith and M. P. Murphy, “Animal and human studies cardiomyopathy: an update,” Heart Failure Reviews, vol. 23,
with the mitochondria-targeted antioxidant MitoQ,” Annals no. 5, pp. 801–816, 2018.
[166] V. Gogvadze, S. Orrenius, and B. Zhivotovsky, “Mitochon-

dria in cancer cells: what is so special about them?,” Trends
in Cell Biology, vol. 18, no. 4, pp. 165–173, 2008.
[167] Q. Cui, S. Wen, and P. Huang, “Targeting cancer cell mito-
chondria as a therapeutic approach: recent updates,” Future
Medicinal Chemistry, vol. 9, no. 9, pp. 929–949, 2017.
[168] B. Kalyanaraman, G. Cheng, M. Hardy et al., “A review of the
basics of mitochondrial bioenergetics, metabolism, and
related signaling pathways in cancer cells: therapeutic target-
ing of tumor mitochondria with lipophilic cationic com-
pounds,” Redox Biol., vol. 14, pp. 316–327, 2018.
[169] J. J. Lemasters, “Evolution of voltage-dependent anion chan-
nel function: from molecular sieve to governator to actuator
of ferroptosis,” Frontiers in Oncology, vol. 7, p. 303, 2017.

Ferroptosis in Different Pathological Contexts

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Oxidative Medicine and Cellular Longevity

V. Otasevic,1 M. Vucetic,2 I. Grigorov,1 V. Martinovic,1 and A. Stancic 1

Correspondence should be addressed to A. Stancic; [email protected]

Academic Editor: Stefano Falone

1. Introduction ways are also the hallmarks of the above-mentioned

BSO Cystine xCT

V Glu Gln Gln

[166] V. Gogvadze, S. Orrenius, and B. Zhivotovsky, “Mitochon-

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