Autophagy

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Mitochondria ROS and mitophagy in acute kidney

injury

Lianjiu Su, Jiahao Zhang, Hernando Gomez, John A Kellum & Zhiyong Peng

To cite this article: Lianjiu Su, Jiahao Zhang, Hernando Gomez, John A Kellum & Zhiyong Peng
(2023) Mitochondria ROS and mitophagy in acute kidney injury, Autophagy, 19:2, 401-414, DOI:
10.1080/15548627.2022.2084862

To link to this article: https://doi.org/10.1080/15548627.2022.2084862

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Published online: 09 Jun 2022.

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AUTOPHAGY
2023, VOL. 19, NO. 2, 401–414
https://doi.org/10.1080/15548627.2022.2084862

REVIEW

Mitochondria ROS and mitophagy in acute kidney injury

# #
Lianjiu Sua,b, , Jiahao Zhanga, , Hernando Gomezc, John A Kellumc, and Zhiyong Peng a,c

a
Department of Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan 430071, China; bBranch, Center for Cancer Research,
National Cancer Institute, National Institutes of HealthNeuro-Oncology, Bethesda, Maryland, USA; cCenter of Critical Care Nephrology, Department
of Critical Care Medicine, University of Pittsburgh Medical Center, Pittsburgh, USA

ABSTRACT ARTICLE HISTORY

Mitophagy is an essential mitochondrial quality control mechanism that eliminates damaged mito­ Received 12 February 2022
chondria and the production of reactive oxygen species (ROS). The relationship between mitochon­ Revised 24 May 2022
dria oxidative stress, ROS production and mitophagy are intimately interwoven, and these processes Accepted 26 May 2022
are all involved in various pathological conditions of acute kidney injury (AKI). The elimination of KEYWORDS
damaged mitochondria through mitophagy in mammals is a complicated process which involves Acute kidney injury; cell
several pathways. Furthermore, the interplay between mitophagy and different types of cell death, death; mitochondria;
such as apoptosis, pyroptosis and ferroptosis in kidney injury is unclear. Here we will review recent mitophagy; reactive oxygen
advances in our understanding of the relationship between ROS and mitophagy, the different species
mitophagy pathways, the relationship between mitophagy and cell death, and the relevance of
these processes in the pathogenesis of AKI.
Abbreviations: AKI: acute kidney injury; AMBRA1: autophagy and beclin 1 regulator 1; ATP:
adenosine triphosphate; BAK1: BCL2 antagonist/killer 1; BAX: BCL2 associated X, apoptosis reg­
ulator; BCL2: BCL2 apoptosis regulator; BECN1: beclin 1; BH3: BCL2 homology domain 3; BNIP3:
BCL2 interacting protein 3; BNIP3L/NIX: BCL2 interacting protein 3 like; CASP1: caspase 1; CAT:
catalase; CCCP: carbonyl cyanide m-chlorophenylhydrazone; CI-AKI: contrast-induced acute kidney
injury; CISD1: CDGSH iron sulfur domain 1; CL: cardiolipin; CNP: 2’,3’-cyclic nucleotide 3’-
phosphodiesterase; DNM1L/DRP1: dynamin 1 like; E3: enzyme 3; ETC: electron transport chain;
FA: folic acid; FUNDC1: FUN14 domain containing 1; G3P: glycerol-3-phosphate; G6PD: glucose-
6-phosphate dehydrogenase; GPX: glutathione peroxidase; GSH: glutathione; GSK3B: glycogen
synthase kinase 3 beta; GSR: glutathione-disulfide reductase; HIF1A: hypoxia inducible factor 1
subunit alpha; HUWE1: HECT, UBA and WWE domain containing 1; IL1B: interleukin 1 beta; IMM:
inner mitochondrial membrane; IPC: ischemic preconditioning; IRI: ischemia-reperfusion injury;
LIR: LC3-interacting region; LPS: lipopolysaccharide; MA: malate-aspartate; MPT: mitochondrial
permeability transition; MUL1: mitochondrial E3 ubiquitin protein ligase 1; mtROS: mitochondrial
ROS; NLR: NOD-like receptor; NLRP3: NLR family pyrin domain containing 3; NOX: NADPH oxidase;
OGD-R: oxygen-glucose deprivation-reperfusion; OMM: outer mitochondrial membrane; OPA1:
OPA1 mitochondrial dynamin like GTPase; OXPHOS: oxidative phosphorylation; PARL: presenilin
associated rhomboid like; PINK1: PTEN induced kinase 1; PLSCR3: phospholipid scramblase 3;
PMP: peptidase, mitochondrial processing; PRDX: peroxiredoxin; PRKN: parkin RBR E3 ubiquitin
protein ligase; RPTC: rat proximal tubular cells; ROS: reactive oxygen species; SLC7A11/xCT: solute
carrier family 7 member 11; SOD: superoxide dismutase; SOR: superoxide reductase; SQSTM1/p62:
sequestosome 1; TCA: tricarboxylic acid; TIMM: translocase of inner mitochondrial membrane;
TOMM: translocase of outer mitochondrial membrane; TXN: thioredoxin; VDAC: voltage depen­
dent anion channel; VCP: valosin containing protein.

Introduction involves multiple stressors including hypoxia, inflammation,

oxidant injury, and other damaging insults, all of which are
Maintaining mitochondrial homeostasis through balanced mito­
known to drive mitophagy induction [4]. In most cases, mito­
chondrial biogenesis and clearance of damaged mitochondria is
a crucial determinant of cellular function. Defective mitochon­ phagy promotes cellular adaptation protecting the cell through
dria can be selectively removed through a specific form of a variety of mechanisms including the elimination of damaged
autophagy, known as mitophagy which is responsible for the mitochondria which are a major source of reactive oxygen
basal mitochondrial turnover to eliminate dysfunctional mito­ species (ROS) generation [5]. Therefore, mitophagy is important
chondria [1]. Mitophagy can be induced in various pathological in kidney injury and is a potential therapeutic target in the
process, such as oxidative stress and inflammation, as a stress- pathogenesis of AKI. A growing number of studies have revealed
response mechanism to inhibit mitochondria-dependent cell the role of mitophagy in kidney diseases [6]. Dysregulation of
death [2,3]. The pathogenesis of acute kidney injury (AKI) also mitophagy results in diverse pathophysiology including cardiac

CONTACT Lianjiu Su [email protected] Department of Critical Care Medicine, Zhongnan Hospital of Wuhan University, 169 Donghu Rd, Wuchang
District, Wuhan 430071, Hubei province, China; Zhiyong Peng [email protected]
#
Contributed equally to this study
© 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/),
which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.
402 L. SU ET AL.

injury, kidney fibrosis and neurodegenerative disease [6–8]. by NOXs can also cause mitochondrial ROS production which is
However, the role mitophagy induction in AKI is not completely an important mechanistic pathways of ROS amplification or
understood. Here, we summarized the role of activation of propagation (summarized in Figure 1) [27].
mitophagy during different causes of kidney injury and the To protect cells from the oxidative stress, enzymatic and
mechanism of mitophagy activation in the kidney, discuss the non-enzymatic defense systems in mitochondria eliminate
excess ROS [28]. The non-enzymatic defense system includes
pharmacologic induction of mitophagy as a potential therapeutic
flavonoids, vitamins, and glutathione [29]. SOD (superoxide
strategy, and provide suggestions for future perspectives in this
dismutase), SOR (superoxide reductase), CAT (catalase), GPX
field. (glutathione peroxidase), GSR (glutathione-disulfide reduc­
tase), PRDX (peroxiredoxin), and TXN (thioredoxin) consti­
tute scavenging enzymes systems that are involved in the
The generation and elimination of mitochondria ROS
regulation of mitochondrial ROS [29]. SOD is in charge of
The main sources of cellular ROS are mitochondria and NOX converting the superoxide anion, the most dangerous ROS
(NADPH oxidase) [9]. Mitochondria utilize oxygen to gener­ produced [30], into hydrogen peroxide, which can be then
ate adenosine triphosphate (ATP) through oxidative phos­ converted to H2O by CAT [30].
phorylation (OXPHOS) which is one of sources of
mitochondrial ROS (mtROS) [10]. The electron transport
The relationship between ROS and mitophagy
chain (ETC) is a series of electron transporters embedded in
the inner mitochondrial membrane (IMM) that shuttle hydro­ Mitophagy is considered a bona fide strategy to limit mtROS
gen ions (H+) across the mitochondrial membrane from the production by removing the aged and damaged mitochondria
mitochondrial matrix into the intermembrane space to gen­ via the specific sequestration and engulfment of mitochondria
erate a potential ionic gradient that contains the energy neces­ in lysosome [31]. Mitophagy may function more broadly to
sary to synthesize ATP. Complex V allows H+ to enter the limit the deleterious effects of ROS on cellular function [32].
mitochondrial matrix in favor of a concentration gradient, ROS induces mtDNA damage, decreases the mitochondrial
releasing the necessary energy to couple phosphate into ade­ membrane potential, and induces oxidation of proteins and
nosine and synthesize ATP [11]. In this process, electrons are lipids [30]. Mitophagy after DNA damage is a vital cellular
transported through the ETC and are finally shuttled to response to maintain mitochondrial functions and DNA
molecular oxygen by complex IV [12]. Leak of electrons at repair. A previous study reported that suppression of mito­
complexes I and III interact with oxygen to produce the phagy disturbs mitochondrial Ca2+ homeostasis, affects ATP
superoxide anion, the most important and dangerous production, and attenuates DNA repair [33]. Mitochondrial
mtROS [13,14]. It is now known that cells produce mtROS proteins and lipids also play important roles in maintaining
as important signaling molecules that participate in physiolo­ mitochondrial function. Specific mitochondrial lipids are cri­
gic functions. However, abnormal increments in the produc­ tical for proper assembly of the electron transport chain
tion of mtROS are known to induce cell injury through complexes and for effective responses to mitophagy [34].
oxidative stress. Besides ATP production, mitochondria are Under stress conditions, cardiolipin (CL), which constitutes
also involved in heme and iron sulfur center biosynthesis almost 20% of the lipid content in the IMM, translocates to
which induce ROS production and play important roles in the outer mitochondrial membrane (OMM) where, together
oxidative damage [15,16]. with ceramide, it binds LC3 and LC3B-II to recruit phago­
NOXs are central components for regulating the cellular phores to damaged organelles (discussed further in the next
redox balance [17]. There are seven isoforms of the NADPH section) [35]. Damage-induced ROS disrupt mitochondrial
oxidases have been identified: NOX1, CYBB/NOX2, NOX3, proteins and damage existing macromolecules. Furthermore,
NOX4, NOX5, DUOX1, and DUOX2 [18]. NADPH is derived these ROS oxidize ergosterol to ergosterol peroxide in the
from the metabolism of glucose through glycolysis wherein OMM [36], which acts as a signal to recruit VCP (valosin
G6PD (glucose-6-phosphate dehydrogenase) is the rate- containing protein) associated mitochondrial stress responsive
limiting enzyme [19]. Pyruvate, the end-product of glycolysis, 1, a component of a mitochondrial surveillance system [37],
is ultimately transported into mitochondria to undergo further to damaged mitochondria for the subsequent signal transduc­
metabolism through the tricarboxylic acid (TCA) cycle generat­ tion to protein degradation by the proteasome which is
ing reduced equivalents in the form of NADH and FADH2 involved in maintaining mitochondrial protein homeostasis
which will then enter the electron transport chain in the last [35]. These data suggest that, oxidation of proteins and lipids
step of oxidative phosphorylation [20]. Complex I catalyzes the should have the presence of adaptive mitophagy for cell to
oxidation of NADPH/NADH generated in the TCA cycle survivor from oxidative damage.
[21,22]. Cytosolic and mitochondrial NADH are exchanged Enhanced mitophagy is usually an early response to pro­
through the malate-aspartate (MA) shuttle and the G3P (gly­ mote survival while overwhelming or prolonged mitochon­
cerol-3-phosphate) shuttle which has been reviewed in previous drial damage can induce excessive, pathological activation of
studies [23–25]. All NOX family members share six highly con­ mitophagy, thereby inducing cell death and tissue injury
served transmembrane domains. The cytoplasmic COOH ter­ [38]. While complex I inhibition stimulates the activation
minus contains conserved NADPH binding domains [26]. The of mitophagy through mtROS generation, subsequent cell
active enzyme complex transports electrons to oxygen from death is ultimately a consequence of mtROS that are mito­
NADPH to produce superoxide free radical [26]. ROS produced phagy- dependent [39]. These data suggest that the process
 AUTOPHAGY 403

of mitophagy may, in some cases, increase mtROS levels conditions focus on the PINK1-PRKN pathway [41].
which could trigger a cell to further induce mitophagy and However, there are PRKN-independent mechanisms that can
therefore propagate the elevation in mtROS levels through trigger the activation of mitophagy including those driving
a positive feedback loop [40]. ubiquitin ligases, receptor and CL.

Molecular regulation of mitophagy PRKN-dependent mitophagy

The best described pathway inducing mitophagy is driven by PRKN, a member of the RING-between-RING family of E3
the enzyme 3 (E3) ubiquitin ligase PRKN (parkin RBR E3 ligases, composed of 14 complex multidomain enzymes which
ubiquitin protein ligase) and the kinase PINK1 (PTEN are mutated in recessive familial forms of Parkinson disease, is
induced kinase 1). The vast majority of the studies investigat­ a key mediator of mitochondrial quality control processes [42].
ing the role of mitophagy in physiological or pathological PINK1, a serine/threonine kinase containing a mitochondrial

Figure 1. The generation and elimination of mitochondria ROS. In the cytosol, NADPH is primarily produced by G6PD in the glycolysis pathway. The cytosolic and
mitochondrial NADPH is exchanged through two shuttles. NOXs transports electrons to oxygen from NADPH to produce superoxide free radical which was converted
by SOD (SOD2 in mitochondria) to hydrogen peroxide, and finally converted by catalase to harmless H2O. Mitochondrial ROS are produced from the leakage of
electrons to form superoxide at complex I and complex III in the electron transport chain. Mitochondria utilize oxygen to generate ATP through OXPHOS.
Abbreviations: ATP: adenosine triphosphate; CAT: catalase; ETC: electron transport chain; G6PD: glucose-6-phosphate dehydrogenase; MA/G3P: the malate-aspartate
(MA) and the glycerol-3-phosphate(G3P) shuttle; NOX: NADPH oxidase; OXPHOS: oxidative phosphorylation; SOD: superoxide dismutase; TCA: tricarboxylic acid.
404 L. SU ET AL.

targeting signal at the N terminus and also plays an important Cardiolipin-mediated mitophagy
role in this process [42]. Normally, PINK1 is constitutively CL is a hallmark mitochondrial lipid which is almost exclu­
imported to the inner membrane via the TIMM (translocase sively found at the IMM [56]. CL can have different roles in
of inner mitochondrial membrane)-TOMM (translocase of mitochondrial quality control and morphology depending on
outer mitochondrial membrane) complex. PINK1 is then its location. When located in the IMM, CL cooperates with
cleaved by several proteases including PMP (peptidase, mito­ OPA1 (OPA1 mitochondrial dynamin like GTPase) to induce
chondrial processing) which removes PINK1’s N-terminal IMM fusion. In response to stress, the mitochondrial PLSCR3
mitochondrial targeting signal and the inner membrane PARL (phospholipid scramblase 3) allows the translocation of CL
(presenilin associated rhomboid like), cleaves PINK1 between from the inner to the outer leaflet of the membrane to bind
amino acids A103 and F104 in its hydrophobic domain span­ directly to LC3 to induce mitophagy [57]. During mitophagy,
ning the IMM, which ultimately results in proteasomal degra­ CL can also interact with BECN1 (beclin 1), a central regu­
dation [43–46]. Mitochondrial membrane potential (ΔΨm) is lator of autophagy, and recruit the autophagic machinery by
a key indicator of mitochondrial health and injury. PINK1 is its interaction with LC3 [58].
imported as normal to the OMM of depolarized mitochondria,
however the loss of ΔΨm prevents its import and subsequent Ubiquitin-mediated mitophagy
cleavage in the IMM [47]. When mitochondrial import is dis­ Mitochondria ubiquitination plays a central role in mitophagy
rupted by depolarization, unprocessed PINK1 accumulates spe­ due to the E3 ligase activity of protein PRKN. Several ubiqui­
cifically at the OMM of dysfunctional mitochondria. In tin ligases other than PRKN have been proved to have com­
response to various stressors, PINK1 accumulates at OMM mon effect with PRKN. MUL1 (mitochondrial E3 ubiquitin
bound to the TOMM complex where it is activated through protein ligase 1) is a resident mitochondrial ubiquitin E3
dimerization and autophosphorylation [48]. PINK1 can stabi­ ligase inserted in the OMM and has a multifunction including
lize on the outer membrane to recruit PRKN from the cytosol to mitochondrial fusion, interplay between the endoplasmic reti­
damaged mitochondria in response to decreased ΔΨm. PINK1 culum and mitochondria and mitophagy [59,60]. MUL1 acts
will phosphorylate PRKN on the Ub-like domain on the Ser in parallel with the PINK1-PRKN pathway in compensate for
resulting in an increase of its E3 activity (Ub ligase activity) and PINK1-PRKN loss in their mutant phenotypes [60]. MUL1
the formation of polyubiquitin chains on the surface of depo­ can act not only as a ubiquitin ligase but also as a mitophagy
larized mitochondrial membranes [49,50]. Activated PRKN receptor. It can directly recruit the autophagy machinery by
polyubiquitinates numerous substrates of OMM proteins, lead­ interaction of GABARAP (GABA type A receptor-associated
ing to the recruitment of the autophagy machinery including protein (Atg8-family protein) [61]. HUWE1 (HECT, UBA
the Ub- and LC3-binding receptor SQSTM1/p62 (sequesto­ and WWE domain containing E3 ubiquitin protein ligase 1)
some 1) (summarized in Figure 2) [51]. has been also identified play a role in AMBRA1-mediated
mitophagy in a PRKN-independent pathway (summarized in
Figure 3) [62].
PRKN-independent mitophagy
Mitophagy in acute kidney injury
Receptor-mediated mitophagy
The OMM exists of several LC3-interacting regions (LIR) con­ The kidney is only second to the heart in mitochondrial
taining autophagic receptors anchored in the membrane of the density and oxygen consumption. This is due to the high-
phagophore [52]. Unlike PINK1-PRKN mediated mitophagy energy demand necessary to reabsorb ~70% of the solute load
requiring the translocation of PRKN to the damaged mitochon­ filtered through the glomerulus and for excretion [63].
dria, some receptors, like BNIP3 (BCL2 interacting protein 3) Increased oxidative stress, inflammation, and uncoupling of
and FUNDC1 (FUN14 domain containing 1), can bind to LC3 oxygen consumption from ATP, all of which are associated
proteins, thereby linking the phagophore to the targeted mito­ with AKI, promote mitochondrial damage which can trigger
chondria, directly inducing mitophagy [52]. This process is mitophagy [63]. While the role of mitophagy in AKI has been
known as receptor-mediated mitophagy. A growing number controversial, many studies have now demonstrated the pro­
of OMM proteins containing LIR domains have also been tective effect of mitophagy in AKI, including PRKN-
identified including BNIP3, its homolog BNIP3L/NIX (BCL2 independent pathways, such as BNIP3-mediated mitophagy
interacting protein 3 like), and FUNDC1, which have been [64] and PRKN-dependent pathways [65]. A few studies have
reviewed previously [41,53]. Proteins in the IMM can also act also reported a damage function of mitophagy in kidney
as crucial mitophagy receptors involved in targeting mitochon­ injury [66]. Some recent reviews have summarized mitochon­
dria for autophagic degradation. PHB2 (prohibitin 2), an IMM drial biogenesis in kidney injury and repair including mito­
protein, binds the phagophore membrane-associated protein phagy [67,68]. The role of mitophagy in various pathological
LC3 through a LIR domain which is required for PRKN- conditions of acute kidney injury is summarized in Table 1.
induced mitophagy in mammalian cells [54]. Some receptors, Abbreviations: AKI: acute kidney injury; BNIP3: BCL2 inter­
like activating molecule in AMBRA1 (autophagy and beclin 1 acting protein 3; BUMPT cells: Boston University mouse proximal
regulator 1) which is a BCL2 homology domain 3 (BH3)-like tubule cells; CCCP: carbonyl cyanide m-chlorophenylhydrazone;
protein, can play a role in the selective degradation of ubiqui­ CKO: conditional knockout; CLP: cecal ligation and puncture;
tylated mitochondria, transducing both canonical PINK1- CNP: 2’,3’-cyclic nucleotide 3’phosphodiesterase; DNM1L: dyna­
PRKN-dependent and -independent mitophagy [55]. min 1 like; FUNDC1: FUN14 domain containing 1; H/R: hypoxia/
 AUTOPHAGY 405

reoxygenation; HIF1A: hypoxia inducible factor 1 subunit alpha; Mitophagy in IR injury

HK-2: human proximal tubular cells; IRI: ischemia-reperfusion
The pathophysiology of renal ischemia-reperfusion injury
injury; KO: knockout; LPS: lipopolysaccharide; MEG3: maternally
(IRI) appears to be characterized by a complex cascade of
expressed 3; NLRP3: NLR family pyrin domain containing 3;
oxidative damage contributing to tubular injury with ultra­
OGD-R: oxygen-glucose deprivation-reperfusion; OPTN: opti­
structural changes in mitochondria [69,70]. Many studies
neurin; PINK1: PTEN induced kinase 1; PRKN: parkin RBR E3
have reported the role of mitophagy during IRI-induced
ubiquitin protein ligase; PTKO: proximal tubule-specific knock­
AKI. The beneficial effect of mitophagy during renal IR was
out; ROS: reactive oxygen species; RPTC: rat proximal tubular
revealed by bnip3 and pink1 knockout mice. BNIP3 has dual
cells; RTEC: renal tubular epithelial cell; RTKN: rhotekin; ULK1:
functions of regulating cell death and mitophagy [71]. Tang
unc-51 like autophagy activating kinase 1
et al. demonstrated that bnip3 deletion have reduced

Figure 2. PRKN-dependent mitophagy. PINK1 is constitutively processed by mitochondrial proteases, PMP and PARL, resulting in its proteasomal degradation in
normal condition (a); In damaged mitochondria, PINK1 accumulates at OMM bound to the TOMM complex where it is activated through auto-phosphorylation.
Activated PINK1 subsequently phosphorylates ubiquitin, which triggers recruitment of PRKN recruitment to mitochondria and activation of its E3 ligase activity. It
further ubiquitinates mitochondrial substrates and initiate autophagosome formation. PRKN acts as an enhancer of this signaling through further ubiquitination of
mitochondrial proteins (b). Abbreviations: IMM: inner mitochondrial membrane; OMM: outer mitochondrial membrane; PARL: presenilin associated rhomboid like;
PINK1: PTEN induced kinase 1; PMP: peptidase, mitochondrial processing; PRKN: parkin RBR E3 ubiquitin protein ligase; SQSTM1/p62: sequestosome 1; TIMM:
translocase of inner mitochondrial membrane; TOMM: translocase of outer mitochondrial membrane.
406 L. SU ET AL.

Figure 3. PRKN-independent mitophagy. Receptor mediated mitophagy: BNIP3, BNIP3L and FUNDC1, are OMM receptors containing an LIR-domain that directly
binds to LC3 proteins to recruit the phagophore to the damaged mitochondria and leading to its degradation; cardiolipin-mediated mitophagy: IMM CL can be
translocated to the OMM through the action of PLSCR3. Once at the OMM, CL binds to LC3A to recruit the phagophore and to remove the damaged mitochondria;
Ubiquitin mediated mitophagy: Some proteins have E3 ubiquitin ligases activities which can be located at damaged mitochondria to ubiquitinate OMM proteins, and
subsequently recruit the phagophore to damaged mitochondria. Abbreviations: BNIP3: BCL2 interacting protein 3; BNIP3L/NIX: BCL2 interacting protein 3 like; CL:
cardiolipin; FUNDC1: FUN14 domain containing 1; E3: enzyme 3; IMM: inner mitochondrial membranes; OMM: outer mitochondrial membranes; LIR: LC3-interacting
region; PLSCR3: phospholipid scramblase 3.

mitophagy resulting in the accumulation of damaged mito­ proximal tubular cells (RPTC) cell and mice induced IRI
chondria, increasing production of reactive oxygen species, model, which suggesting that mitophagy plays an important
cell death and inflammation in oxygen-glucose deprivation- role in the protective effect of IPC [72]. DNM1L/DRP1 (dyna­
reperfusion (OGD-R) and IRI model [64]. Tang and his co- min 1 like) translocated to mitochondria and was phosphory­
authors proved that PINK1-PRKN-mediated mitophagy plays lated at S616 in response to IRI [73]. Inhibiting DNM1L
an important role in mitochondrial quality control, tubular phosphorylation significantly suppressed without affecting
cell survival, and renal function in both in vitro and in vivo general autophagy suggesting that DNM1L was involved the
models of ischemic AKI [65]. Knockdown of pink1 sup­ process of mitochondrial fragmentation and downregulation
pressed mitophagy and reduced the cytoprotective effect of of mitophagy significantly aggravated kidney dysfunction
ischemic preconditioning (IPC) when treated carbonyl indicating that mitophagy was activated via DNM1L-
cyanide m-chlorophenylhydrazone (CCCP) in the rat dependent pathway to protect cells from IRI-induced
Table 1. The role of mitophagy in various pathological conditions of acute kidney injury.
Pathways Factors Model Cells and Animals Mechanisms Effect Reference
PRKN-dependent IRI CCCP for HK-2 cells and IRI for mice PINK1 siRNA, PRKN siRNA, or double siRNA in cells; pink1-KO, prkn-KO 1. Reduce mitochondrial damage Activation of mitophagy [65]
or double-KO in mice. 2. Modulate the removal of ROS protects against AKI
3. Relieve inflammatory response
4. Modulate cell death
IRI H/R for HK-2 cells and IRI for mice PmirGLO-Dual-luciferase reporter vector of MEG3 and RTKN in cells; Promoting apoptosis Activation of mitophagy [66]
AAV-sh-MEG3 vector in mice via tail vein. aggravates AKI
IRI CCCP for RPTC cells and IRI for mice Pink1 shRNA in cells 1.Suppressed mitochondrial Activation of mitophagy [72]
PT-atg7-KO in mice depolarization protects against AKI
2.Improved ATP production
3.Inhibited the generation of ROS
Sepsis LPS for RPTC cells and LPS or CLP for Pink1 siRNA, Prkn siRNA, or Optn siRNA in cells; pink1-KO or prkn KO 1. Mitochondrial quality control Activation of mitophagy [81]
mice in mice 2. Reduce cells apoptosis protects against AKI
Sepsis LPS for RPTC cells Pink1 siRNA and Prkn siRNA in cells 1. Inhibited the apoptosis Activation of mitophagy [82]
2. Remove damaged mitochondria protects against AKI
Sepsis LPS for HK-2 cells and CLP for rats PRKN siRNA or SIRT1 inhibitor in HK-2 cells; Prkn silencing lentivirus 1. Inhibited the apoptosis Activation of mitophagy [83]
and SIRT1 inhibitor EX527 in rats via tail vein 2. Inhibited the pyroptosis protects against AKI
3. Remove damaged mitochondria
Sepsis CLP for mice prkn-KO in mice 1. Inhibition of mitochondrial Activation of mitophagy [84]
dysfunction protects against AKI
2. Inhibition of NLRP3 inflammasome
activation
Cisplatin Cisplatin injected intraperitoneally pink1-KO or prkn-KO in mice Reduce cells apoptosis Activation of mitophagy [87]
for mice protects against AKI
Cisplatin Cisplatin for RTECs and cisplatin - 1. Reversed cellular ROS induced by Activation of mitophagy [88]
injected intraperitoneally for mice cisplatin protects against AKI
2. Reversed mitochondrial membrane
potential level induced by cisplatin
Cisplatin Cisplatin for HK-2 PINK1 siRNA, PRKN siRNA and PINK1 or PRKN overexpression plasmids 1. Protected against mitochondrial Activation of mitophagy [89]
in HK-2 dysfunction protects against AKI
2. Protected against cell injury
Cisplatin Intraperitoneal injection of cisplatin pink1-KO in rats 1. PINK1 deficiency inhibited DNM1L- Excessive mitophagy [90]
for rats mediated mitochondrial fission aggravates AKI
2. PINK1 deficiency inhibited excessive
mitophagy
Contrast Iohexol for HK-2 and iohexol PINK1 siRNA or PRKN siRNA in cells; pink1-KO or prkn-KO in mice 1. Reduce mitochondrial ROS Activation of mitophagy [91]
administration for mice 2. Reduce NLRP3 inflammasome protects against AKI
activation
Contrast Ioversol for HK-2 and ioversol for - 1. Reduce oxidative stress Activation of mitophagy [94]
rats 2. Reduce mitochondrial damage protects against AKI
PRKN-independent IRI OGD-R for BUMPT cells and IRI for Bnip3 silence in cells; bnip3-KO in mice 1. Eliminate damaged mitochondria Activation of mitophagy [64]
mice 2. Modulate the removal of ROS protects against AKI
3. Modulate cell death
4. Relieve inflammatory response
IRI IRI for rats Mdivi-1, an inhibitor of DNM1L, in rats 1. Mitophagic clearance of damaged Activation of mitophagy [73]
mitochondria protects against AKI
2. Protects cells apoptosis.
IRI IRI for mice cnp-KO in mice. Aggressive removal of injured Activation of mitophagy [74]
mitochondria protects against AKI
IRI H/R for HK-2 cells and IRI for mice HIF1A siRNA, BNIP3 siRNA, and BNIP3-overexpression plasmid for cell; 1. Inhibited apoptosis Activation of mitophagy [75]
hif1a-CKO and bnip3-overexpression adenovirus in mice 2. Inhibited ROS production protects against AKI
IRI IRI for mice and rotenone for fundc1-PTKO, dnm1l-PTKO, ulk1-PTKO and fundc1-dnm1l-PTKO in 1. Mitochondrial quality control Activation of mitophagy [76]
AUTOPHAGY

primary tubule cells mice 2. Reduce ROS oxidative stress protects against AKI
3. Reduce mitochondrial apoptosis
Contrast Iohexol for HK-2 and iohexol BNIP3 siRNA in cells; bnip3-KO in mice Reduce cells apoptosis Activation of mitophagy [93]
administration for mice protects against AKI
407
408 L. SU ET AL.

apoptosis [73]. Similar results were obtained with cnp 2’,3’- PRKN shown the contrary phenomenon suggesting mito­
cyclic nucleotide 3’-phosphodiesterase) deletion mice which phagy plays a cytoprotective role against cisplatin injury
attenuates IRI-induced AKI, in part by accelerating mito­ [89]. However, Liu et al reported that pink1 deficiency
phagy with targeted removal of damaged mitochondria [74]. ameliorated cisplatin-induced AKI in rats, possibly via
Fu et al reported that BNIP3 overexpression reversed the inhibiting DNM1L-mediated mitochondrial fission and
inhibitory effect of HIF1A (hypoxia inducible factor 1 subunit excessive mitophagy [90].
alpha) knockout on mitophagy and prevented enhanced kid­
ney damage in vivo and vitro [75]. Wang and his co-authors
demonstrated that FUNDC1-dependent mitophagy, primarily Mitophagy in response to contrast
driven by IPC, confers resistance to AKI through reconcilia­
Iodinated intravascular contrast is widely used for vessel
tion of mitochondrial fission in a rotenone treated model
and chamber imaging in coronary angiography and per­
in vitro and IRI model in vivo [76]. However, Zhou et al
cutaneous intervention. Despite advancements in imaging
reported that activation of mitophagy also aggravates kidney
and interventional techniques, contrast-induced acute kid­
ischemia-reperfusion injury by trigger the WNT-CTNNB1
ney injury (CI-AKI) occurs in more than 30% of patients
/beta-catenin pathway in vitro and vivo [66].
after intravenous iodinated [91,92]. Mitophagy has been
shown to play an important role in CI-AKI. Lin et al
Mitophagy in response to sepsis reported that PINK1-PRKN-mediated mitophagy pre­
vented apoptosis and tissue damage in CI-AKI in vitro
Sepsis is defined as organ dysfunction resulting from the
and vivo through reducing mitochondrial ROS and sub­
host’s deleterious response to infection and one of the
sequent NLRP3 (NLR family, pyrin domain containing 3)
most common organs affected is the kidney [77]. Sepsis
inflammasome activation [91]. BNIP3-mediated mito­
and inflammation at the tissue and cellular level are asso­
phagy also has the protective function in CI-AKI [93].
ciated with decreased levels of intracellular ATP and with
Some drugs have the protective effect in CI-AKI by reg­
mitochondrial injury in various organs, including the kid­
ulating mitophagy. Bae et al reported that paricalcitol, an
ney [78]. Ultrastructural changes are observed in mito­
active vitamin D analogue, could play a renoprotective
chondria during sepsis-induced AKI including decreased
role against CI-AKI through the PRKN-dependent path­
mitochondrial mass, disruption of cristae, and extensive
way [94]. Tetramethylpyrazine can be protective against
mitochondrial swelling [79]. Sepsis also induces profound
CI-AKI because it can ameliorate renal oxidative stress
alterations in kidney tubular epithelial cell metabolism and
and aberrant mitochondrial dynamics, and modulate
in peritubular capillary flow distribution, all of which can
mitophagy in tubular cells in vitro and vivo [95]. Ward
result in significant energy imbalance and further mito­
et al showed that the radiocontrast agent diatrizoic acid
chondrial injury [80]. Importantly, mitophagy is activated
could induce mitophagy and oxidative stress via calcium
early in the course of sepsis, providing the cell with
dysregulation, however, the role of the mitophagy in this
a mechanism to remove damaged mitochondria which is
process has not been further investigated [96].
important to minimize cell injury and accelerate recovery
[78]. Several studies demonstrated that PRKN-dependent
pathway of mitophagy was induced in in mouse models of
Mitophagy in the other drug-induced AKI
septic AKI induced by lipopolysaccharide (LPS) treatment
or by cecal ligation and puncture or in cultured proximal Many drugs can induce AKI, including some that are
tubular epithelial cells exposed to LPS, which plays an classically used as models of AKI such as folic acid (FA)
important role in mitochondrial quality control, tubular and oxalate. The role of mitophagy in the pathobiology of
cell survival, and renal function in septic AKI [81–84]. AKI from these drugs is poorly understood. However,
These protective effect of mitophagy in sepsis induced previous studies indicated that mitochondria play
AKI could be attributed to a decreasing inflamma­ a critical role in their cytotoxicity to kidney. Zhang et al
tion [85]. reported that inhibition of mitochondrial complex
I activity aggravated renal tubular injury, mitochondrial
damage and oxidative stress in FA-induced AKI [97]. This
Mitophagy in response to cisplatin
cytotoxicity effect of FA may due to trigger a mitophagy
Cisplatin is a widely used chemotherapeutic drug with dependent ROS increase leading to cell death [39].
notorious toxicity to the kidneys, which involves mito­ Mitophagy interfaces with mitochondrial biogenesis to
chondrial dysfunction and damage in renal tubular cells. regulate mitochondrial content and longevity [98].
Mitophagy induction and its cytoprotective role have been During the FA-induced kidney injury, the mitochondrial
demonstrated both in vitro and in vivo in models of biogenesis was suppressed and mitochondrial dysfunction
cisplatin-induced AKI [86–88]. Both pink1 and prkn is persistent to promote the progression of kidney injury
knockout mice showed more severe renal functional loss, [99]. Acute oxalosis displayed calcium oxalate crystals
tissue damage, and apoptosis during cisplatin treatment inside distal tubular epithelial cells caused AKI associated
[87]. In vitro, knockdown of PINK1-PRKN induced the with mitochondrial changes characteristic of mitochon­
aggravation of mitochondrial function, leading to the drial permeability transition [100], which can finally lead
increase of cell injury, while the overexpression of PINK1- to mitophagy [101].
 AUTOPHAGY 409

Figure 4. Crosstalk between mitophagy and other type of cell death. VDAC regulates mitochondria iron homeostasis through CISD1 which may affect the iron-
dependent cell death of ferroptosis. Translocator protein interacts with VDAC in PINK-PRKN-dependent mitophagy. VDAC gate the Ca2+ transport to control energy
production and metabolism by modulating enzyme activity of TCA which impacts the production of mitochondria ROS in the electron transport chain. GSK3B
increased VDAC phosphorylation to control MPT. SLC7A11/xCT regulates extracellular cystine and intracellular glutamate exchanging which influence the TCA and
GSH metabolism through glutamate and cystine, respectively. BCL2 family proteins regulate apoptosis through controlling the assembly of multimeric BAX-BAK1
channels. The interaction of BECN1-BCL2 inhibits autophagy and mitophagy but increase apoptosis. BCL2 family proteins, like BNIP3, can disrupt interaction between
the BECN1 and antiapoptotic BCL2 family. NLRP3 process pro-CASP1 to active CASP1, which cleaves pro-inflammatory IL1B to mature IL1B causing pyroptosis. NLRP3
binding of its LIR motif to LC3 induce mitophagy while CASP1 inhibits mitophagy to amplify mitochondrial damage. VDAC activates NLRP3 to induce pyroptosis.
Abbreviations: BAK1: BCL2 antagonist/killer 1; BAX: BCL2 associated X, apoptosis regulator; BCL2: BCL2 apoptosis regulator; BECN1: beclin 1; CASP1: caspase 1;
CISD1: CDGSH iron sulfur domain 1; GPX: glutathione peroxidase; GSH: glutathione; GSK3B: glycogen synthase kinase 3 beta; IL1B: interleukin 1 beta; LIR: LC3-
interacting region; MPT: mitochondrial permeability transition; NLRP3: NLR family pyrin domain containing 3; PINK1: PTEN induced kinase 1; PRKN: parkin RBR E3
ubiquitin protein ligase; SLC7A11/xCT: solute carrier family 7 member 11; TCA: tricarboxylic acid; VDAC: voltage dependent anion channel.

Interplay of mitophagy, apoptosis, pyroptosis and mechanism of interaction between mitophagy and various cell
ferroptosis in AKI death forms.
Mitophagy is mainly thought of as a survival mechanism by Both mitophagy and apoptosis are generally induced in
response to a common stimulus. The crosstalk between mito­
removing damaged mitochondria and related ROS from these
phagy and apoptosis is mediated by several key molecules
damaged mitochondria. In addition to elimination of damaged
including members of the BCL2 (BCL2 apoptosis regulator)
mitochondria, mitophagy prevents cell death by regulating genes family and its interacting protein like BNIP3 and FUNDC1,
associated with programmed cell death [32], which is a general and other mitophagy-related proteins. BCL2 family proteins
410 L. SU ET AL.

regulate apoptosis by controlling the assembly of multimeric [120]. Cystine is a source of the synthesis of the glutathione
BAX (BCL2 associated X, apoptosis regulator)-BAK1 (BCL2 (GSH) which is a cofactor of the GPX4 [119]. Thus, on the
antagonist/killer 1) channels and thereby, modulating the one hand, erastin targets the SLC7A11 receptor on membrane
permeability of the OMM [102]. BCL2 regulates macroauto­ to influence the activity of GPX4 to induce ferroptosis. On the
phagy through binding to the autophagy regulator BECN1 by other hand, it can also activate VDAC receptor located at
interacting with its BH3-only domain and blocking its parti­ mitochondrial outer membrane to increase Ca2+ transport
cipation in the triggering of autophagosome formation. BCL2 which controls energy production and metabolism by mod­
family proteins have also been proved to inhibit PINK1- ulating critical enzymes in the TCA cycle [121]. Besides,
PRKN-dependent mitophagy [103]. Some BCL2-interacting glutamate can transfer to α-Ketoglutarate through alanine
proteins like BNIP3 and FUNDC1 that disrupt interaction aminotransferase which is involved in TCA cycle [122].
between the BECN1 and antiapoptotic BCL2 family to pro­ Thus, mitochondria may play an important role in the cross­
mote positive regulation of mitophagy [104,105]. In a renal talk between mitophagy and ferroptosis.
IRI model, BNIP3 in kidney cell induced light chain 3 expres­ Increasing evidence shows that mitochondrial dysfunction
sion and formation of autophagosomes which were mainly has an important role in ferroptosis [123–125]. GSK3B (gly­
localized to the mitochondria, suggesting that mitophagy is cogen synthase kinase 3 beta) resides at the nexus of multiple
induced in renal tubules by BNIP3, which may be activated to signaling pathways implicated in the regulation of mitochon­
protect the renal tubules during IRI-AKI [106]. BCL2 binding drial permeability transition (MPT) which finally caused
to BECN1 is known to inhibit autophagy [107]. Disruption of mitochondrial clearance though mitophagy [39,126]. GSK3B
BECN1-BCL2 interactions can enhance of autophagy activity increased VDAC phosphorylation, key MPT regulators
to protect kidney from ischemia-reperfusion injury [108]. located at OMM, and sensitized cells to MPT during drug-
BCL2 family proteins inhibits apoptosis and autophagy in induced oxidant stress kidney injury [127]. VDAC is an
kidney injury has been largely investigated [109–111]. important protein in the crosstalk between mitophagy and
BNIP3, inhibit mitophagy, and enhancing apoptosis and ferroptosis, and serves as a mitochondrial docking site to
ROS production during IRI [75]. recruit PRKN from the cytosol to defective mitochondria to
Pyroptosis is a pro-inflammatory form of regulated cell induce mitophagy [128]. The translocator protein interacts
death and is dependent on the enzymatic activity of inflam­ with VDAC1 which plays an important role in PINK1-
matory proteases that belong to the family of cysteine- PRKN-dependent mitophagy [129]. This procedure may be
dependent aspartate-specific proteases (caspases) [112]. enrolled during the kidney injury. VDAC was reported as the
Mitochondrial components are recognized as danger- only channel-forming protein and allowed the metabolites
associated molecular patterns by cytosolic pattern recognition and irons across the outer membrane, erastin-induced
receptors such as NOD-like receptors family member of VDAC opening mediated mitochondrial iron uptake may
NLRP3 inflammasomes [113]. They process pro-CASP1 (cas­ accelerate ferroptosis [130]. MitoNEET, also referred to as
pase 1) to active CASP1, which cleaves pro-inflammatory CISD1 (CDGSH iron sulfur domain 1), a redox-sensitive
IL1B (interleukin 1 beta) to mature IL1B causing inflamma­ (2Fe-2S) cluster protein, is an OMM protein essential for
tion and cell death by pyroptosis. NOD-like receptor (NLR) sensing and regulation of iron and ROS homeostasis [131].
family member with a mitochondrial targeting sequence, con­ CISD gates VDAC when oxidized in a redox-dependent man­
tains a LIR and binding of its LIR motif to LC3 induce ner in cells, closing the pore and likely disrupting flow of iron
mitophagy [114,115]. Another study demonstrated that [132]. Mitochondrial TCA plays an important role in mito­
NLRP3 activators induced mitochondrial damage, leading to phagy and ferroptosis. The flux of respiratory substrates,
their PRKN-dependent mitophagy [116]. Inhibition of NLRP3 ADP, and Pi into mitochondria and the release of mitochon­
inflammasome activation was dependent on PRKN-mediated drial ATP to the cytosol occur through voltage-dependent
mitophagy in sepsis-induced acute injury [84]. CASP1 inhibits anion channels [39]. Thus, inhibition VDAC caused mito­
mitophagy to amplify mitochondrial damage, mediated in chondrial TCA cycle inhibition which mitigate mitochondrial
part by cleavage of the key mitophagy regulator PRKN membrane potential hyperpolarization, lipid peroxide accu­
[117]. Mitochondria dysfunction induced NLRP3 activation. mulation and triggers a mitophagy-dependent ROS increase
Both ROS generation and inflammasome activation are sup­ leading to ferroptosis (summarized in Figure 4) [39,133,134].
pressed when mitochondrial activity is dysregulated by inhi­
bition of the VDAC (voltage dependent anion channel) [118].
Conclusion
These studies indicated that mitophagy removed damage
mitochondria caused by pyroptosis is a compensatory Mitophagy is a key cellular homeostatic mechanism that is
mechanism to the pyroptotic cell death through the interplay activated early during AKI. The effect of mitophagy and the
protein of NLRP3 and CASP1. relationship between mtROS levels and mitophagy are per­
Ferroptosis is a form of cell death that results from the haps more complicated. During AKI, mitophagy is activated
catastrophic accumulation of lipid ROS caused by inactive early through PRKN-dependent and independent signaling
GPX4 and the accumulation of iron [119]. Erastin, a special pathways. The activation of mitophagy is protective in this
ferroptosis inducer, targets cystine/glutamate antiporter context, removing dysfunctional mitochondria from TEC and
SLC7A11/xCT (solute carrier family 7 member 11), to inhibit decreasing thereby local inflammation and oxidative damage.
extracellular cystine and intracellular glutamate exchange The crosstalk between mitophagy and forms of cell death such
 AUTOPHAGY 411

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