Fcell 12 1347286
Fcell 12 1347286
Fcell 12 1347286
1 Introduction
Throughout history, aging has been a major concern for society. Healthcare advances
and the distribution of vaccines have contributed to the increase in life expectancy from
35 years in the 18th century to 72.6 years today (Nakamura et al., 2017; Mansouri
Torghabeh et al., 2022). Based on numerous observations, it has been hypothesized that
the poor quality of reproductive cells can result in accelerated aging and a shorter
Abbreviations: CAT, catalase; CM, cristae membrane; Drp1, dynamin related protein 1; FADH2, flavin
adenine nucleotide phosphate; FUNDC1, FUN14 domain containing1; GC, granulosa cell; GPX,
glutathione peroxidase; GSR, glutathione reductase; IBM, inner boundary membrane; ICS, intracristal
space; IMM, inner membrane; IMS, intermembrane space; Mfn1/2, mitofuscin 1/2; mtDNA,
mitochondrial DNA; NADH, nicotinamide adenine dinucleotide hydride; OMM, outer membrane; OS,
oxidative stress; OxPhos, oxidative phosphorylation; PRDX, peroxiredoxin; ROS, reactive oxygen species;
SOD, superoxide.
healthspan (Loose et al., 2022). The state of the reproductive system and the integrity of mitochondrial DNA (mtDNA) also play
is not only essential for fertility, but also for overall health. significant roles (Terman et al., 2007; Noh et al., 2023). Delayed
Reproductive aging is a universal developmental process blastocyst development and reduced quality in gametes are
conserved across species coinciding with age-related fertility associated with accumulated oxidative damage and inefficient
depletion and decline of gamete quality, culminating in infertility clearance of dysfunctional mitochondria (Shen et al., 2021; Khan
and deleterious consequences on the offspring (Drori and Folman, et al., 2023). Importantly, there is a high probability that these issues
1976; Drewry et al., 2011; Archie et al., 2014; Sinha and Rae, 2014). are interconnected.
Reproduction is an energy-costly undertaking that profoundly Here, we provide an overview of the evidence that explain how
impacts on multiple individual characteristics at molecular, mitochondrial function and OS can affect reproductive function and
cellular, and endocrine levels (Loose et al., 2022; Secomandi the rate at which it undergoes cellular age-related alterations.
et al., 2022). Nevertheless, reproductive fitness also offers notable
physiological benefits. For instance, it is commonly discovered that
women who remain reproductively healthy until their late 30 years 2 Mitochondria and ROS
or even 40 years have longer lifespans compared to younger women
who give birth in their late 20 years (Murphy, 2023). Similarly, 2.1 The structure and functions of
research on humans indicates that early menopause may be mitochondria
associated with increased mortality (Shuster et al., 2010). Despite
the presence of numerous intrinsic and extrinsic factors that may Mitochondria are ubiquitous intracellular organelles present in
contribute to aging traits in an organism’s germline, the intricate nearly all eukaryotes and involved in multiple aspects of cellular life,
cellular mechanisms underlying reproductive aging remain poorly with a primary role in energy production. This functional diversity is
understood and warrant further investigation to fully comprehend reflected in the complicated mitochondrial ultrastructure (Figure 1).
the complex interactions involved. Mitochondria, unlike most organelles, are highlighted by their
In recent academic research, there is a growing emphasis on the possession of two distinct membranes: an outer membrane
role of mitochondria as a central component in cellular events (OMM) that encloses the organelle and interfaces with the
associated with reproductive aging primarily due to oxidative cytosol, and an inner membrane (IMM) that displays
stress (OS) caused by the progressive accumulation of ROS, as a morphological complexity. The IMM can be further subdivided
result of oxidative phosphorylation (OxPhos) (Gumienny et al., into two components: the inner boundary membrane (IBM), which
1999; Terman et al., 2007; Roger et al., 2017). Nevertheless, OS is not is closely attached to the outer membrane, and the cristae membrane
the sole contributing factor to mitochondria-dependent changes in (CM), which forms lamellar or tubular protrusion within the
reproductive aging; energy metabolism, mitochondrial dynamics, organelle. These membranes give rise to distinct compartments
FIGURE 1
Mitochondrial ultrastructure and the vicious loop among extensive ROS, mito-structural damage, and mitochondrial dysfunction (partially refer to
Iovine et al., 2021). Mitochondrion is precisely compartmentalized, which can be divided into mtDNA, membrane compartments and aqueous
compartments. The membrane compartments include OMM, IBM, and CM from the outside in. The aqueous parts contain IMS, ICS, and the innermost
matrix. Respiratory chain present within the IBM is composed of CI to V, which undergoes OxPhos for material and energy metabolism accompanied
by ROS production. Once ROS is produced extensively and accumulated constantly in cells, ROS would damage the vulnerable mtDNA and
mitochondrial inner structure, leading to mitochondrial dysfunction and more ROS. mtDNA, mitochondrial DNA; OMM, outer membrane; IBM, inner
boundary membrane; CM, cristae membrane; IMS, intermembrane space; ICS, intracristal space; CI to V, Complex I to V; AQP, aquaporin; VDAC, voltage-
dependent anion channel.
within the mitochondria, including the intermembrane space (IMS) energy derived from the oxidation of hydrogen carriers is effectively
located between the OMM and the IBM, the intracristal space (ICS) conserved in the form of ATP (Figure 1).
enclosed by the CM, and the innermost matrix (Iovine et al., 2021). From the Free radical theory of aging proposed by Harman early
Particularly, mitochondria possess their own DNA, which encodes in 1956 focusing to the endogenous free radicals to the polished
numerous vital proteins necessary for the assembly and operation of Mitochondrial theory of aging developed to include all forms of ROS
mitochondrial respiratory complexes. MtDNA is especially today, intense research has approved that cumulative oxidative
vulnerable to stress-induced damage believed to be a result of the damage contributes to physiological deterioration and ultimately
absence of histones in structure and limited effectiveness of repair leads to aging and death, and mitochondria play an equally
mechanisms (Kim et al., 2015; Vadakedath et al., 2023). important role (Harman, 1956; Lee and Wei, 2001; Salmon et al.,
Mitochondria are involved in essential functions of the cell, 2010; Holmstrom and Finkel, 2014). Concurrent alterations in ROS
including energy metabolism, substance metabolism, signal level and mitochondrial morphology have been reported in
transduction, intracellular calcium homeostasis, cell apoptosis numerous experimental studies. For example, muscle- and skin-
(Iovine et al., 2021). Energy metabolism and material metabolism derived fibroblasts with an inactive Complex I exhibit an elevated
within mitochondria are synchronized. Mitochondria produce high- ROS level and progressive mitochondrial fragmentation
energy phosphorylated substance ATP into all cellular characterized by reduced mitochondrial length and branch,
compartments through a complex interconnected metabolic whereas patient cells without Complex I deficiency display only
network (TCA cycle, OxPhos, and fatty acid β-oxidation) using controllable ROS levels and a normal mitochondrial morphology
multiple energy sources, such as amino acids, lipids, and (Koopman et al., 2007; Blanchet et al., 2011). The excessive presence
carbohydrate derivatives (Heldt, 1972; Wang J. et al., 2009). of ROS heightens the likelihood of mutations of mtDNA that
Mitochondria possess the ability to modulate energy production encodes proteins related to the respiratory chain, ultimately
via glycolysis, the TCA cycle, and OxPhos in response to alterations affecting ATP production and potent kinetic energy supply for
in cellular energy demands (Lim et al., 2011). Furthermore, motion (Venkatesh et al., 2009). Collectively, mitochondria as the
mitochondria assume a pivotal role in the regulation of primary generators and the recipients of oxidative damage, implies a
intracellular signaling (Tan and Finkel, 2020). As a Ca2+ buffer vicious cycle wherein impaired mitochondria produce increased
zone within cells, mitochondria collaborate with the endoplasmic amounts of ROS, in turn leading to a progressive accumulation of
reticulum, extracellular matrix, and other cellular structures by damage that culminates in the process of aging (Figure 1).
Controlling the Ca2+ concentration to modulate cellular activities In all cells, an intracellular balance between the production and
(Aoyama-Ishiwatari and Hirabayashi, 2021). Additionally, elimination of ROS, known as “redox homeostasis”, necessitates
mitochondria participate in the regulation of various cellular efficient coordination of reactions across various cells and is
stress responses, such as OS, heat stress, and apoptosis (Chien regulated by an intricate network of pro-oxidation and
et al., 2014; Yao et al., 2023). The proper execution of antioxidant systems (Chianese and Pierantoni, 2021). The latter,
mitochondrial functions counts on the structural the source of total antioxidant capacity, encompasses non-
compartmentalization, which allows mitochondria to respond to enzymatic scavengers, as well as detoxifying enzymes that operate
intracellular signals timely. Over the past decade, substantial within distinct organelles. Non-enzymatic antioxidants include
evidence has emerged, shedding light on the involvement of albumin, urate, taurine, hypotaurine, pyruvate, lactate,
mitochondria in gamete formation and embryonic development, tocopherol, ergothioneine, ascorbic acid and melatonin (Ball,
as well as the elevated prevalence of reproductive disorders, such as 2008; Gonzalez-Arto et al., 2016). The antioxidant enzyme
inflammation of genitourinary system (Jankauskas et al., 2018), defense system involves superoxide dismutase (SOD), catalase
asthenospermia (Li et al., 2023), and polycystic ovary syndrome (CAT), glutathione peroxidase (GPX), glutathione reductase
(Jiang et al., 2022). (GSR), peroxiredoxin (PRDX), and so on (Ben Abdallah et al.,
2009; Klopotowska et al., 2022). OS is defined as the imbalance
between the detoxification of cell antioxidant defense system and the
2.2 Mitochondria as the major source of ROS production of ROS. In the status of OS, extensive ROS is produced
generation and accumulate within the whole cell. ROS is extremely reactive and
can engage in reactions with virtually any substantial molecules,
In eukaryotes, the production of ATP occurs within leading to lipid peroxidation and DNA impairment, among other
mitochondria through oxidative metabolism of nutrients, which consequences (Yang et al., 2010). Polyunsaturated fatty acid
involves two key steps: OxPhos process (Iovine et al., 2021), and the moieties of phospholipids and cholesterol are preferred substrates
oxidation of nicotinamide adenine dinucleotide hydride (NADH) or for lipid hydroperoxides (e.g., Malonaldehyde and 4-
flavin adenine nucleotide phosphate (FADH2), or the β-oxidation of hydroxynonenal) and OH generated in membranes (Brouwers
fatty acids (Shen et al., 2017). The electron transport chain facilitates et al., 2005). Active ROS attacks directly sensitive DNA and
the oxidation of NADH and FADH2 generated through glycolysis damages components of the chromosome, such as telomeres,
and the TCA cycle. Simultaneously, it actively transports protons causing DNA strand breaks and altered repair mechanisms that
across the IMM, leading to the accumulation of protons in the IMS. can lead to the acquisition of genomic changes (Sallmyr et al., 2008).
This process establishes a transmembrane proton gradient with These impaired molecules disrupt regular cellular metabolism,
proton-motive force. Complex V (or called ATP synthase), prompting a subsequent escalation in ROS production, thus
harnesses the proton flow driven by this gradient to catalyze the establishing a detrimental cycle. Ultimately, the excessive
synthesis of ATP from ADP and phosphoric acid. Consequently, the accumulation of ROS culminates in oxidative damage to
macromolecules, cells, and even the overall structure and surveillance, repair, and proteolytic pathways, it is noteworthy
functionality of the organism (Redza-Dutordoir and Averill- that these defense systems are susceptible to age-related
Bates, 2016). impairments, thereby diminishing their capacity to effectively
eliminate proteins damaged by oxidation (Peters et al., 2020).
ROS-induced damage can impact the primary molecular
3 Effects of excessive ROS levels on constituents of oocytes, encompassing lipid membranes, nucleic
reproductive aging acids, and protein complexes, thereby disrupting protein
functionality and cellular equilibrium (Husain and Mahmood,
3.1 The role of ROS in oocyte quality and 2019; Cui et al., 2022). Increased ROS can also cause structural
female fertility deterioration of organelles, leading to mitochondrial dysfunction,
telomere shortening due to decreased telomerase activity,
ROS plays a dual role in oocyte development, serving as both a abnormalities in spindle assembly, and abnormal cytoskeletal
beneficial and detrimental factor. In its normal functioning, ROS dynamics (Zhang et al., 2018; Zhou et al., 2019). These abnormal
assumes a crucial role in regulating folliculogenesis, meiosis, conditions significantly diminish the effectiveness of meiotic
ovulation, and embryonic development by acting as secondary recombination, resulting in errors in chromosome segregation
messengers in cellular signaling pathways (Agarwal et al., 2012). and loss (Liu et al., 2004; Schatten and Sun, 2015; Yang et al.,
However, when present in excessive amounts, ROS will result in OS 2020). Consequently, oocytes undergo abnormal meiotic division
and exert detrimental effects including a series of reproductive and experience a substantial decline in egg quality (Figure 2).
diseases such as endometriosis and polycystic ovary syndrome The absence of antioxidant genes in the ovaries can disrupt
(Wang F. et al., 2023; Weng et al., 2023; Zhou et al., 2023). The follicular growth. Histological analysis conducted on the ovaries
initial proposition by Tarin (Tarin, 1995) regarding ovarian from SOD1 knockout mice demonstrated many primary and small
senescence posits that oocytes exhibit reduced resistance to ROS, antral follicles but few corpora lutea (Matzuk et al., 1998). Deletion
which is a significant contributor to oocyte impairment. The of SOD1 resulted in a defect in implantation of embryos to the wall
prolonged duration of meiosis-arrested oocytes increases their of the uterine horns and small litters, suggesting that SOD1 may play
vulnerability to oxidative damage, as indicated by the disturbance a critical role in germ cell survival (Ho et al., 1998). The gilts supplied
of protein homeostasis, particularly in terms of proteolysis (Wu for dietary 2-hydroxy-4-methylselenobutanoic acid showed
et al., 2022). Even though oocytes possess the capability to increased weight of uteri accompanied by increased the activity
counteract this effect through the activation of intricate of T-AOC, T-SOD, GPX, TXNRD and decreased MDA content in
FIGURE 2
Detrimental effects of excessive ROS and mitochondrial dysfunction on different reproduction stages from gamete formation to embryonic
development in the uterus. For the male, excessive ROS and mitochondrial dysfunction would cause inactive sperms with loss of fertility and declined
motility by decreased energy supplement to fail to sperm penetration. For the female, excessive ROS and mitochondrial dysfunction would influence the
entire oogenesis, increase the possibility of lessened quantity of ovum, and decline fertilization potential. Otherwise, excessive ROS can disturb the
fetal development and even occurs developmental disorders. A solid arrow indicates that the process is normal, and a dashed arrow indicates that the
process is defective.
granulosa cells (GCs), implied that the drug is conducive to and elevated levels of ROS and malondialdehyde, which can be rescued
promoting follicle development by antioxidant pathway (Lin by the antioxidants N-acetyl-L-cysteine or tocopherol (Chen et al.,
et al., 2022). Furthermore, many advantageous factors from 2022). These studies indicate that antioxidant enzymes in the sperm
environment like resveratrol can elevate the level of ROS to storage organ play a strong protective role against OS ensuring
generate various intracellular toxic effects including embryonic maintenance of sperm vitality and overall quality. Understanding the
stage cellular toxicity and teratogenicity in various mammalian regulatory mechanisms of the endogenous oxidative defense system,
species and even the impact on human fetal development which serves as the primary barrier against high OS in sperm, is of
(Manzo et al., 2010; Auti et al., 2022). In recent years, more and significant value for improving reproductive capacity.
more drugs have been evidenced playing a significantly antioxidant
role to help delay or rescue the aging phenotypes of reproduction
(Yang et al., 2022; Wang et al., 2023b; Wang et al., 2023c). For 4 Mitochondrial dysfunctions
instance, the antioxidant Salidroside can increase the number of associated with reproductive aging
blastocyst cells, the proliferation of blastocysts, and the expressions
of pluripotency genes while reducing ROS levels in oocytes and 4.1 Consequences of inadequate
enhancing intracellular GSH levels (Shi et al., 2023). Currently, mtDNA levels
screening of drugs to effectively decrease the level of ROS possesses a
broad prospect to ameliorate the quality of oocytes and their Mammalian mitochondria are naturally inherited through the
subsequent embryonic development. maternal lineage (Hutchison et al., 1974), whereas the sperm
mitochondria become degraded after fertilization (Sutovsky et al.,
1999). Hence, the determination of oocyte health, fertilization, and
3.2 The role of ROS in sperm functions and early embryonic development hinges on the abundance and quality of
testis health the mitochondrial population within the oocyte to a great extent (Wai
et al., 2010; Fragouli and Wells, 2015). The quality as well as the number
The decline in male reproductive function with age is a prevalent of mitochondria within the oocyte play significant roles as markers for
phenomenon observed in mammals, birds, and flies (Fricke and Koppik, oocyte quality and pivotal indicators for fertilization and embryo
2019). Research conducted on males have revealed that aging poses development (Tilly and Sinclair, 2013). During the process of oocyte
smaller testes (Mahmoud et al., 2003), a notable decrease in the average growth subsequent to follicle recruitment, the primordial oocyte
quantity of sertoli cells (Johnson et al., 1984), and lower testosterone experiences a substantial increase in the number of mitochondria
levels (Pines, 2011). A retrospective analysis of semen parameters (e.g., (Wassarman et al., 1976). Hence, the replication of mtDNA and
ejaculate volume, sperm concentration, and sperm motility), conducted mitochondrial biogenesis is sustained in parallel with the follicle
on a sample size exceeding 5,000 men aged 16–72 years indicates semen growth (Larsson et al., 1998; Hou et al., 2019). According to
parameters commence a decline after 34 years of age (Stone et al., 2013). estimations, there is a decline of approximately 4 copies of human
Sperm quality, as one of the decisive factors affecting animal mtDNA every 10 years, which has been associated with compromised
reproductive capacity, is crucial for the propagation across species. post-implantation development and an elevated likelihood of
The abnormal increase of ROS in the reproductive system by age is subfertility (Zhang et al., 2017; Busnelli et al., 2018). The analysis of
one of the core causes of the decline of sperm quality. an in vitro fertilization/intracytoplasmic sperm injection program
Once ROS levels increase abnormally, it can lead to decreased suggested the circulating level of anti-Müllerian hormone, a
fluidity of the mitochondrial membrane structure, protein denaturation, hormone essential to the regulation of ovarian follicle growth by
and increased membrane fragility within the sperm (Fleury et al., 2002). inhibiting initial follicle recruitment, is strongly correlated with
This disruption can directly result in the inability to maintain the proton mtDNA abundance within GCs (Bowolaksono et al., 2022). The
gradient across the inner mitochondrial membrane, causing the accumulating evidence from current studies exhibits that an
biochemical basis of ATP synthesis to be compromised. As a result, association exists between maternal age and the incidence of
sperm loses its motility and ability to move effectively due to decreased mtDNA deletion in oocytes and GCs (Keefe et al., 1995; Chan et al.,
energy levels (Chianese and Pierantoni, 2021). In order to cope with the 2005). Additionally, a greater number of mtDNA copies in the embryo
risk of high OS, sperm have developed a unique oxidative defense is linked to higher fecundity (Murakoshi et al., 2013; Babayev et al.,
mechanism to maintain low levels of ROS within their internal 2016). Generally, the inadequate amount of mtDNA is insufficient in
environment (Guerriero et al., 2014; O’flaherty, 2019). Besides supplying the required energy reserves for follicular growth,
providing a liquid environment for sperms, seminal plasma serves as consequently resulting in oocyte degeneration.
a source of numerous nutrients and protective substances that modulate
sperm capacitation and gamete interaction (Vashisht and Gahlay,
2023). Among multitudinous substances, antioxidant system is high- 4.2 Consequences of abnormal
profile for their roles involved in the process (Yin et al., 2023). In the mitochondrial dynamics for the
seminal plasma of jackasses, the activities of antioxidant enzymes (SOD, development of reproductive system
CAT, GPX, and GSR) were significantly correlated with sperm motility
and forward movement ability (Maehly and Chance, 1954; Wdowiak Mitochondria are organelles characterized by their dynamic
et al., 2015; Papas et al., 2019). The impairment by NiCl2 treatment on nature with an intricate network of tubular structures, displaying
sperm total motility and progressive motility in a dose- and time- an amazing plasticity of morphology and distribution.
dependent manner is characterized by interference with Ca2+ signaling Mitochondrial dynamics includes the fusion and fission between
the IBM and the OM during mitochondrial movement with embryonic genome may necessitate mitochondrial fusion to
surrounding mitochondria for exchange of matrix and membrane facilitate this significant developmental process. Inhibition of
components (Wai and Langer, 2016). The two pivotal events Drp1 in embryonic stem cells induced totipotency-to-
maintain a continuously coordinated cycle essential for pluripotency transition characterized by decreased activity of the
facilitating adequate local energy generation and distribution glycolysis/gluconeogenesis pathway by failed silencing of 2-cell
required by each cellular organelle to execute their respective genes in embryos, ultimately leading to impeded development of
functions (Frederick and Shaw, 2007). This enables mitochondria early embryos (Guo et al., 2023). High expression of Mfn1
to preserve its optimal functioning status and structural integrity significantly promoted early development of bovine embryos with
(Suen et al., 2008). Fusion serves to alleviate stress by amalgamating somatic cell nuclear transfer by increasing ATP level and
the constituents of partially impaired mitochondria, thereby mitochondrial membrane potential, while reducing H2O2
enhancing their functionality, while fission is necessary for the generation by improving OxPhos (Babayev et al., 2016).
elimination of compromised and less efficient mitochondria or Mitochondrial fission and fusion homeostasis are critical factors
for the generation of novel ones (Karbowski et al., 2002). ensuring the optimal mitochondrial activity in oocytes and embryos,
Assessing the impact of mitochondrial fusion and fission on thereby facilitating the normal development of embryos, and
cellular processes proves challenging due to the multifaceted preventing oxidative damage. With the identification and
nature of these processes, which can yield diverse outcomes validation of additional molecules or drugs, the manipulation of
dependent on the temporal and spatial factors of their mitochondrial dynamics may emerge as a prospective avenue for
occurrence. It is worth noting that mitochondria are highly improving reproductive health.
prevalent organelles in oocytes and embryos. Throughout
maturation of oocytes and embryonic development preceding
implantation, mitochondria undergo persistent and dynamic 4.3 Disruption of mitochondrial
modifications to facilitate essential cellular developmental events bioenergetics for oocyte maturation
(Sathananthan and Trounson, 2000; Harvey, 2019). The actional
nature of energy demands leads to corresponding fluctuations in It is well known that mitochondria are key regulators of
mitochondrial dynamics, which effectively and unitedly regulate structure formation, metabolic activity, and function (Sherratt,
metabolism to meet the material and energy requirements necessary 1991). Their most primary role, energy production, is critical for
for oocyte maturation and embryonic development (Schatten et al., function of organs with high metabolism like ovary and testis. The
2005; Zhao et al., 2016). oocyte possesses a greater quantity of mitochondria compared to
The involvement of mitochondrial dynamic-related proteins in other cells in mammals (Kim et al., 2019). Research using
germ cells and embryos has been investigated extensively in mammalian models has provided compelling evidence that
mammals. The novel evidence from mitofuscin 2 (Mfn2) mitochondria are imperative for the development of proficient
knockout mice indicates that the seminiferous tubules display a female gametes. During the maturation of follicles, as the
vacuous morphology due to impaired spermatogenesis and efficiency of glycolysis in the oocyte is limited due to low
increased apoptosis, parallel to an interference of cellular expression of phosphofructokinase (Leese and Barton, 1984),
respiration effected by lower expression of the subunits of there is a metabolic shift from glycolysis to OxPhos, which
OxPhos complexes (Wang X. et al., 2021). facilitates the production of increased ATP levels conducive to
Indeed, it has been empirically shown that, alongside supporting various processes such as cytoplasmic and nuclear
mitochondrial fusion, the process of fission is also necessary in maturation, spindle formation, and polar body extrusion
governing the preservation of early spermatogenesis (Honda and (Barbehenn et al., 1974; Zhang et al., 2006; Dumollard et al.,
Hirose, 2003). Stage-specific enhancement in dynamin related 2007b). In this stage, there is a significant increase in the
protein 1 (Drp1) expression in rat spermatids cooperated with abundance of functional mitochondria, which serves as the
Mfn2 to trigger the mitochondrial ubiquitination to attain their primary provider of ATP for the reorganization of cytoplasmic
homogenization by fusion and fission. The Drp1-deleted oocytes and nuclear activities, such as gene expression and the initiation of
displayed clustering of aberrant mitochondria, compromised crucial signaling cascades (Kirillova et al., 2021). Additionally, the
calcium homeostasis, impaired secretory function, multiorganelle spatial arrangement of mitochondria undergoes a transformation,
deformation, disrupted meiosis, and ultimately, age-dependent transitioning from a homogenous distribution throughout the
infertility in female mice (Udagawa et al., 2014). Mitofuscin 1 cytoplasm during the germinal vesicle stage to a clustered
(Mfn1) knockout oocytes exhibited impaired oocyte-GC aggregation near the perinuclear region in metaphase I or II
communication, downregulated cadherins and connexins, oocytes (Wang L. Y. et al., 2009).
resulting in follicle developmental arrest at the secondary follicle Previously, it has been documented that there is a notable rise in
stage as well as depletion of ovarian follicular reserve. These ATP level alongside the clustering of mitochondria in the
phenotypes could be partially rescued by treatment with perinuclear region during the maturation of oocytes in mice and
ceramide synthesis inhibitor myriocin (Zhang et al., 2019). pigs (Yu et al., 2010). Inefficient mitochondrial bioenergetics can
Targeted deletion of Mfn2 in mice showed reduced rates of contribute to a detrimental impact on the effectiveness of
oocyte maturation and fertilization, along with changes in bidirectional signal communications between GCs and oocytes,
mitochondrial allocation and spindle assembly (Liu et al., 2016), primarily mediated by the secreted sex hormones and
which highlighted the involvement of mitochondrial dynamics in intercellular gap junctions (Best et al., 2015). Consequently, this
regulating chromosome separation in oocytes. The activation of the disruption may result in impairments in oocyte maturation. In
addition, it has been demonstrated that a decline in ATP content the sex difference in lifespan expectancy: the accumulation of
generated through OxPhos process can impede the cytoplasmic mtDNA mutations may potentially make an adverse consequence
microtubule network, leading to a delayed or hindered maturation for males if they are neutral or advantageous for females (Innocenti
of oocytes in mice (Marques-da-Silva et al., 2011). Disruption of et al., 2011). These effects may manifest directly, such as through
OxPhos, the core process for ATP production, can cause halting of mitochondrial function (Anderson et al., 2022), or indirectly, such as
oocyte maturation, chromosomal misdistribution, and hindered retroegulation of nuclear genome by mtDNA (Hamalainen et al.,
embryo development (Takeuchi et al., 2005; Thouas et al., 2006; 2019). However, the substantial variations in the reproductive cycle
Wyman et al., 2008).The conditional disruption of the decaprenyl and the pace of reproductive senescence among males and females
diphosphate synthase subunit 2 (Pdss2) gene, leading to a deficiency have yet to be adequately elucidated and warrant further
of CoQ in oocytes, overviews numerous phenotypic alterations investigation.
typical of mitochondrial dysfunction in oocytes associated with
reproductive aging, and could be reversed by the administration
of CoQ10 (Ben-Meir et al., 2015). During the matured phase of 5.2 ROS and mitochondria interact in
oocyte, mitochondria undergo relocation to varying regions to fulfill ovarian aging
localized energy requirements. The occurrence of rapid increases in
ATP demand and subsequent mitochondrial redistribution are The female reproductive longevity is predominantly influenced
closely linked to the development of the oocyte (Figure 2). An by the ovarian health. A shortened reproductive longevity in female
adequate number of functional mitochondria makes up a decisive with diminished fertility or potential infertility can be attributed to
factor in determining the quality of the oocyte. the accelerated ovarian aging. Ovarian aging is characterized by a
decline in oocyte quality, as well as a decrease in the quantity of
follicles and oocytes. The theory of ovarian aging, initially proposed
5 Discussion by Tarin, posits that oocytes exhibit a reduced capacity to withstand
ROS, a crucial factor contributing to oocyte impairment (Tarin,
5.1 Variations in the rates of reproductive 1995). At a fundamental level, ROS functions as a secondary
aging exist between males and females messenger in cellular signaling and assumes a crucial role in
facilitating folliculogenesis, meiosis, and ovulation processes (Ellis
In mammals, the process of reproduction can be categorized into et al., 1987). However, the detrimental effects of excessive ROS can
distinct stages, namely, sex differentiation, sexual maturation, germ adversely affect the fundamental molecular components of oocytes,
cell development encompassing spermatogenesis and oogenesis, leading to the disruption of protein functionality and cellular
mating, fertilization, pregnancy, and parturition. The lifespan homeostasis (e.g., telomerase) (Sasaki et al., 2019). The two hit
expenses of sustaining reproductive capability, and of “telomere theory of reproductive aging” proposed that oocytes
reproduction itself primarily focus on maintaining a stable experience a greater accumulation of environmental and
developmental environment and ensuring an adequate energy endogenous oxidative damage throughout the lifetime of female
supply, as any deviation or mistake at any stage can impede individuals, which could be mediated by telomeres (Robinson et al.,
successful reproduction (Zhang and Hood, 2016). The 2023). Telomeres undergo elongation through two distinct
completion of reproduction necessitates the collaborative efforts mechanisms, telomerase and alternative lengthening of telomeres.
of both females and males, although females typically assume greater Alternative lengthening of telomeres is infrequently observed except
responsibilities, such as embryonic development, parturition, and telomeropathy. Sperms harbor the longest telomeres in the body,
lactation. Intriguingly, in the context of human reproduction, men which are continuously generated by a telomerase-active progenitor,
exhibit a prolonged fertility span throughout their lives, consistently spermatogonia, throughout the male’s lifespan. In contrast, the
generating sperm, whereas women experience a comparatively telomerase activity in the female germline is initially low and
limited window of fertility. The decline in female fertility decreases following the initiation of meiotic arrest (Liu et al.,
commences around the age range of 30–35, manifesting in an 2007; Jeon et al., 2022). Otherwise, telomere attrition may still
augmented likelihood of miscarriage, diminished chances of occur due to the presence of ROS (Kordowitzki, 2021).
conception, and an expedited progression of reproductive Therefore, oocytes frequently carry short telomeres trapped into
senescence, characterized by an increased probability of oocyte a risky survival situation. Even though this theory has some
aneuploidy (Mogessie, 2020). The different reproductive aging rationality, ROS may interact with the health of oocytes in more
patterns between sexes may be associated with the global aspects than just telomere length. The disruption caused by ROS will
phenomenon that women outlive men worldwide (Thornton, trigger endoplasmic reticulum stress, autophagy, and proteasome
2019). Sex differences in life expectancy also share a a prevalent dysfunction, culminating in follicular atresia and a decline in both
trend in many species, including mammals (Hoffman et al., 2013), the quality and quantity of oocytes (Sasaki et al., 2019). Furthermore,
birds (Liker and Szekely, 2005), and insects (Bateman, 1948). Males mitochondrial quality determines the potential of oocyte fertility
may be sacrificing access to resources to longer lifespan expectancy and the developing embryo (Dumollard et al., 2007a). Mitochondrial
in favor of sustaining an extended reproductive potential. One dysfunction can give rise to heightened ROS level and the
explanation for trade-offs between longevity and reproduction is accumulation of damaged age-related proteins (Seli et al., 2019).
that male sex hormones reduce the lifespan of men, proved by a Excessive ROS levels can prompt intracellular OS and contribute to a
longer lifespan in castrated men (Min et al., 2012). Asymmetric decline in the quantity of primordial follicles and the mortality of
inheritance of mtDNA presents a novel perspective for explaining pre-implantation embryos, consequently diminishing the
reproductive lifespan of females (Sasaki et al., 2019). The interplay transgenic mice showed that sperm mitochondria are not
between ROS, mtDNA damage, and mitochondrial dysfunction subjected to elimination by the early embryonic degradation
establishes a vicious cycle (Figure 1), the occurrence of which can mechanisms, ubiquitin-proteasome, and autophagy. Instead,
initiate a cascading effect-an increase in ROS levels and mtDNA sperm mitochondria may persist uniformly in certain cells
mutagenesis, ultimately resulting in a decline in until the morula stage, suggesting paternal mtDNA could be
reproductive capacity. transmitted to offspring (Luo et al., 2013). Indisputably,
mitochondria play a crucial role in the processes of sperm
fertility and fertilization, and any aberration within the
5.3 The role of paternal mitochondria in mitochondria has the potential to cause impairment of sperm
offspring development fertility and subsequent male infertility.
can delve into the causes of reproductive aging and disorders, paving Funding
the way for effective therapeutic strategies.
The author(s) declare financial support was received for the
research, authorship, and/or publication of this article. This work
6 Future perspectives was supported by the National Natural Science Foundation of China
(Nos. 32272939 and 31830094, and 31902215); Natural Science
The factors driving diverse aging phenotypes, especially Foundation of Chongqing, China (No. cstc2021jcyj-cxtt0005);
concerning reproductive aging, are expected to be complex, High-level Talents Program of Southwest University
involving changes across various physiological systems. Although (SWURC2021001); and China Agriculture Research System of
we can differentiate between extrinsic and intrinsic factors, it is likely MOF and MARA (No. CARS-18-ZJ0102).
that the levels of ROS and mitochondrial quality associated with
reproductive aging are influenced by both forces, suggesting a
significant interplay between them. Delving into the intricate
interplay among ROS, mitochondria, and germline function will
Conflict of interest
yield valuable insights into underlying molecular mechanism of
The authors declare that the research was conducted in the
reproductive aging. Further exploration is also conducive to lay the
absence of any commercial or financial relationships that could be
groundwork to address fertility issues in humans by exploring
construed as a potential conflict of interest.
potential strategies from the point of ROS level and mitochondria.
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