Biophysical Reviews

https://doi.org/10.1007/s12551-021-00891-w

REVIEW

Uncovering the important role of mitochondrial dynamics

in oogenesis: impact on fertility and metabolic disorder transmission
Marcos Roberto Chiaratti1

Received: 5 September 2021 / Accepted: 1 November 2021

© International Union for Pure and Applied Biophysics (IUPAB) and Springer-Verlag GmbH Germany, part of Springer Nature 2021

Abstract
Oocyte health is tightly tied to mitochondria given their role in energy production, metabolite supply, calcium (­ Ca2+) buffer-
ing, and cell death regulation, among others. In turn, mitochondrial function strongly relies on these organelle dynamics once
cyclic events of fusion and fission (division) are required for mitochondrial turnover, positioning, content homogenization,
metabolic flexibility, interaction with subcellular compartments, etc. Importantly, during oogenesis, mitochondria change
their architecture from an “orthodox” elongated shape characterized by the presence of numerous transversely oriented
cristae to a round-to-oval morphology containing arched and concentrically arranged cristae. This, along with evidence
showing that mitochondrial function is kept quiescent during most part of oocyte development, suggests an important role
of mitochondrial dynamics in oogenesis. To investigate this, recent works have downregulated/upregulated in oocytes the
expression of key effectors of mitochondrial dynamics, including mitofusins 1 (MFN1) and 2 (MFN2) and the dynamin-
related protein 1 (DRP1). As a result, both MFN1 and DRP1 were found to be essential to oogenesis and fertility, while MFN2
deletion led to offspring with increased weight gain and glucose intolerance. Curiously, neither MFN1/MFN2 deficiency
nor DRP1 overexpression enhanced mitochondrial fragmentation, indicating that mitochondrial size is strictly regulated
in oocytes. Therefore, the present work seeks to discuss the role of mitochondria in supporting oogenesis as well as recent
findings connecting defective mitochondrial dynamics in oocytes with infertility and transmission of metabolic disorders.

Keywords Oocyte · Mitochondria · Endoplasmic reticulum · MFN1 · MFN2 · DRP1

Introduction et al. 2008). The mitochondrion presents in this context as a

In humans, the ovary is one of the first organs to fail with
aging due to a progressive reduction of both follicle (the
functional unit of the ovary) number and egg quality. Con-
sequently, live birth rate declines from 43%, among women
younger than 35 years, to 6%, among women aged 42 years
or more (Baird et al. 2005; Schwartz and Mayaux, 1982;
Van Noord-Zaadstra et al. 1991; Wright et al. 2008). While
the decline in follicle number is thought to be explained
by increased follicle atresia as a result of programed cell
death (apoptosis), meiotic errors resulting in aneuploidy
are the leading cause of poor egg quality (Schwartz and
Mayaux, 1982; Van Noord-Zaadstra et al. 1991; Wright
* Marcos Roberto Chiaratti
marcos.chiaratti@ufscar.br
1
Departamento de Genética e Evolução, Centro de Ciências
Biológicas e da Saúde, Universidade Federal de São Carlos,
São Carlos 13565‑905, Brazil
pivotal organelle due to its key role in apoptosis and energy
production for normal spindle assembly and chromosomal
segregation (Al-Zubaidi et al. 2021; Babayev et al. 2016;
Bentov et al. 2011; Johnson et al. 2007; May-Panloup et al.
2016; Pasquariello et al. 2019; Tilly and Sinclair, 2013;
Van Blerkom et al. 1995, 2000; Yu et al. 2010). In addition,
numerous metabolic processes regulated by mitochondria
such as calcium (­ Ca2+) buffering, phospholipid biosynthe-
sis, and reduction–oxidation state can affect egg formation
(Al-Zubaidi et al. 2021; Carroll et al. 1994; May-Panloup
et al. 2016; Spinelli and Haigis, 2018). In face of these find-
ings, mitochondrial quality and number have been proposed
as markers of egg quality. Indeed, there are several reports
showing that mitochondrial DNA (mtDNA) copy number
can be highly variable among oocytes (and, consequently,
embryos) and associate with developmental potential,
although further studies are needed to verify the extension
and reliability of this association (Diez-Juan et al. 2015; Fra-
gouli et al. 2015; Pasquariello et al. 2019; Santos et al. 2006;

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Vol.:(0123456789)

Seli 2016; Wai et al. 2010). Moreover, several attempts have
been made to rescue poor quality eggs through supplemen-
tation with exogenous mitochondria, being their results a
matter of constant debates (Cohen et al. 1997; Kristensen
et al. 2017; Labarta et al. 2019a, b; Woods and Tilly, 2015).
The mitochondrial network can vary from hundreds to
millions of mitochondria depending on the cell type and
on the balance between mitochondrial fusion and fission
(division). In turn, each mitochondrion is composed of two
membranes, the inner and the outer, which delimitate two
compartments, the mitochondrial lumen (matrix) and the
intermembrane space; invagination of the inner membrane
towards the matrix further determines the mitochondrial
cristae (reviewed by (Pernas and Scorrano, 2016)). Within
the mitochondrial matrix resides the enzymes taking part
in the tricarboxylic acid cycle and β-oxidation, biochemi-
cal processes responsible for the oxidation of energetic sub-
strates. Nicotinamide adenine dinucleotide (NAD)H and
flavin adenine dinucleotide (FAD)H2, generated from these
oxidative processes, sustain the electron transport chain
(ETC) through four enzymatic complexes in the cristae
membrane, enabling reduction of oxygen ­(O2) into water
as well as the formation of a proton ­(H+) gradient across
the inner mitochondrial membrane. Eventually, the ­H+ gra-
dient is used by a fifth enzymatic complex (the F ­ 1F0-ATP
synthase) in the cristae membrane to phosphorylate ADP
into ATP, this latter representing the most abundant energy
source for biological processes in the cell. In addition to
ATP, reactive oxygen species (ROS) such as hydrogen
peroxide, superoxide, and hydroxyl radicals can be gener-
ated from the oxidative phosphorylation (OXPHOS) due
to incomplete ­O2 reduction. ROS can damage membranes,
proteins, and nucleic acids, but the mitochondrion owns a
highly effective mechanism for dealing with its production.
Under certain circumstances, however, ROS production sur-
passes the mitochondrial oxidative defenses, with potential
consequences to mitochondrial and cellular health (reviewed
by (May-Panloup et al. 2016)).
The majority of the mitochondrial proteome (~ 1100 pro-
teins) is encoded in the nucleus, translated in the cytoplasm,
and imported into mitochondria (Rath et al. 2020). None-
theless, mitochondria have their own genome (mtDNA),
which in mammals is exclusively inherited from the mother,
has ~ 16.5 kb, and encompasses 37 genes encoding for 13
polypeptides of the OXPHOS complexes (reviewed by
(Stewart and Chinnery, 2020)). Additionally, recent works
suggest a role for mtDNA in encoding mitochondrial derived
peptides (MDPs) and small mitochondrial RNAs (Miller
et al. 2020; Pozzi et al. 2019). Multiple mtDNA copies are
present in each cell, being mtDNA copy number closely
associated with the cell’s energy demand. One or more cop-
ies of mtDNA are packaged together along with proteins
such as the mitochondrial transcription factor A (TFAM) to
13
Biophysical Reviews
form a nucleoid, a likely platform for replication, transcrip-
tion, and translation of mtDNA (reviewed by (Gustafsson
et al. 2016)). Due to its relative short half-life, mtDNA is
replicated at a correspondingly high rate, making it prone
to replicative errors (Krasich and Copeland, 2017). As such,
mutated mtDNA can coexist in a cell with wild-type mol-
ecules (referred to as heteroplasmy), potentially leading to
devastating diseases (reviewed by (Craven et al. 2017)).
The present work aims to review the current knowledge
regarding the role of mitochondria in supporting oocyte
development. Several works encompassing morphofunc-
tional characteristics of oocyte mitochondria are discussed,
with an emphasis on recent findings connecting defective
mitochondrial dynamics in oocytes with infertility and inter-
generational transmission of metabolic disorders.
The unique characteristics of mitochondria
in oocytes
Oogenesis commences with specification of primordial germ
cells (PGCs) in the posterior epiblast base in pre-gastrula-
tion post-implantation embryos. Thereafter, PGCs migrate
to the gonadal ridges, differentiate into oogonia, and pro-
liferate by mitosis prior to undergoing meiosis and giving
rise to oocytes (reviewed by (Kobayashi and Surani, 2018)).
Oocytes progress through the first stages of meiosis until
reaching the late-diplotene resting stage referred to as dicty-
ate; meiosis is resumed only after puberty, which in humans
can take 40 years or more. At birth, the ovary is therefore
populated with up to hundreds of thousands of oocytes sur-
rounded by a single layer of squamous somatic granulosa
cells (Fig. 1). These germ-soma structures, called primordial
follicles, remain quiescent until they are recruited for devel-
opment, which encompasses proliferation and differentiation
of granulosa cells along with a ~ 100-fold increase in oocyte
volume (Liu et al. 2014; Pedersen and Peters, 1968; Reddy
et al. 2008; Rimon-Dahari et al. 2016; Zhang and Liu, 2015).
During this period, known as folliculogenesis, the oocyte
progresses through a series of changes and stockpiles sev-
eral molecules and organelles, events that rely on the close
interaction of the gamete with granulosa cells (Fig. 1). Even-
tually, the oocyte resumes meiosis and is ovulated at the
metaphase II stage (Fig. 1), even though many oocytes can
be eliminated through follicle atresia (reviewed by (Binelli
and Murphy, 2010; Clarke, 2017)).
While mitochondria in PGCs have a rounded shape
(0.4–0.6 μm in diameter) and tubulo-vesicular cristae, these
organelles get enlarged (0.8–1.0 μm in diameter) after differ-
entiating into oogonia, besides owing sparse, lamellar cristae
(Motta et al. 2000). In turn, during oocyte differentiation,
mitochondria assume an “orthodox” (Fig. 1) configuration
characterized by an elongated shape (1.2–1.9 μm in length)
Biophysical Reviews
Primordial Primary Tertiary
follicle follicle follicle
granulosa
cells
oocyte
granulosa cell
granulosa cell
(squamous)
(cuboid)
vacuole oocyte
dumbbell-shaped
mitochondrion
granulosa cell-
oocyte coupling
“orthodox” rounded
mitochondrion mitochondrion
Fig. 1  Unique characteristics of mitochondria in oocytes. Starting
with puberty, a group of primordial follicles initiates development
as represented by proliferation and differentiation of somatic granu-
losa cells as well as oocyte growth. This period, known as follicu-
logenesis, encompasses several stages (i.e., primary, secondary, and
tertiary follicles) and eventually should result in the ovulation of a
gamete competent for fertilization and embryogenesis. In turn, mito-
chondrial architecture changes dramatically during oocyte develop-
ment. Initially, mitochondria display an “orthodox” configuration
characterized by an elongated shape, (1.2–1.9 μm in length), numer-
ous transversely oriented cristae, and a single large vacuole. However,
the increased abundance of dumbbell-shaped mitochondria in early-
developing oocytes indicates a change in mitochondrial dynamics that
results, near ovulation, in mitochondria that are round (0.4–0.6 μm in
diameter), vacuolated, and have arched and concentrically arranged
and numerous transversely oriented cristae, apart from a sin-
gle large vacuole (Wassarman and Josefowicz, 1978). These
morphological changes, which are suggestive of increased
OXPHOS capacity, are, however, transient as dumbbell-
shaped mitochondria become abundant in early develop-
ing oocytes (Fig. 1), eventually giving rise to round/oval
vacuolated organelles displaying columnar-shaped, arched
cristae (Wassarman and Josefowicz, 1978). Following,
mitochondria in fully developed oocytes remain round/oval
(0.4–0.6 μm in diameter), contain a large vacuole, and have
arched/concentrically-arranged cristae (Fig. 1) (Trebichalská
et al. 2021; Wassarman and Josefowicz, 1978). It is worth
noting that in ruminants such as cows, mitochondria assume
a singular hooded morphology in oocytes, with unclear func-
tional consequences (Fair et al. 1997). Moreover, as oocytes
develop, mitochondria, the smooth endoplasmic reticulum
(ER), and lipid droplets become more frequently associated
(Fig. 1), pointing towards an important role of such orga-
nelle cluster (referred to as metabolic units) in late oogenesis
(Kruip et al. 1983; Motta et al. 2000; Trebichalská et al.
2021).
About one hundred thousand mitochondria are estimated
in fully-grown oocytes, which represents a ~ 1000-fold
Ovulation
ZP
ER
lipid
droplets
cristae. Moreover, as oocytes develop, mitochondria, the smooth
endoplasmic reticulum (ER), and lipid droplets become more fre-
quently associated, pointing towards an important role of such orga-
nelle cluster (referred to as metabolic units) in late oogenesis. These
changes in mitochondrial morphology, along with functional data,
suggest that mitochondrial activity is downregulated through oogen-
esis. In agreement with this, granulosa cells generate multiple filopo-
dia (arrowheads in the inset) that penetrate the zona pellucida (ZP)
to reach the oocyte membrane and establish gap/adherens junctions.
Apart from acting as a signaling hub, these cell junctions are used
by granulosa cells to provide the gamete with energetic molecules
such as ATP, pyruvate, nicotinamide adenine dinucleotide phosphate
(NADP)H, cholesterol, and certain amino acids. The inset in “Ovula-
tion” depicts an ovulated oocyte with mitochondria stained in green
and visualized through confocal microscopy (scale bar = 25 μm)
increase compared to the number in PGCs (Cao et al. 2007;
Jansen and De Boer, 1998; Motta et al. 2000; Wai et al.
2008; Wassarman and Josefowicz, 1978). Although this
enormous population has been attributed to an essential role
of the organelle (Harris et al. 2009), mitochondrial density
decreases with folliculogenesis progression (Babayev et al.
2016). Moreover, growing oocytes have fragmented mito-
chondria and poorly developed mitochondrial cristae and are
only slightly affected by PDHA1 deficiency (Johnson et al.
2007; Kruip et al. 1983; Motta et al. 2000; Tarazona et al.
2006; Trebichalská et al. 2021; Wassarman and Josefowicz,
1978), collectively suggesting that mitochondrial activity is
likely downregulated in oocytes. Indeed, there are several
reports showing that both pyruvate consumption (normal-
ized by oocyte volume) and mitochondrial-coupled oxygen
consumption decrease with oocyte development (Biggers
et al. 1967; Eppig, 1976; Harris et al. 2009; Hashimoto
et al. 2017; Magnusson et al. 1986; Porterfield et al. 1998;
Thompson et al. 1996; Trimarchi et al. 2000). Therefore, it
is believed that the gamete is kept at a relatively quiescent
catabolic status due to the action of granulosa cells in pro-
viding the oocyte with several energetic molecules, includ-
ing ATP, pyruvate, NAD phosphate (NADP)H, cholesterol,
13

and certain amino acids (Fig. 1) (Biggers et al. 1967; Downs,
1995; Eppig et al. 2005; Johnson et al. 2007; Richani et al.
2021; Su et al. 2007, 2009; Sugiura et al. 2007). Accord-
ingly, reprogramming of somatic cells into a pluripotent
state is paralleled by a metabolic switch characterized by
fragmentation of the mitochondrial network and decreased
mitochondrial activity (Chen and Chan, 2017; Cho et al.
2006; Ma et al. 2015a; Prigione et al. 2014; Son et al. 2015).
On the other hand, mitochondrial-coupled ATP formation is
essential for resumption of meiosis, spindle formation, and
chromosome segregation, likely due to end of granulosa cell-
oocyte cooperation near ovulation (Abbassi et al. 2021; Al-
Zubaidi et al. 2019; Brevini et al. 2005; Dalton et al. 2014;
Downs, 1995; Downs et al. 2002; Krisher and Bavister,
1998; Kruip et al. 1983; Pasquariello et al. 2019; Stojkovic
et al. 2001; Van Blerkom et al. 1995; Yu et al. 2010).
Main effectors of mitochondrial dynamics
A large body of evidence has implicated mitochondria in
a range of complex biological processes encompassing
cellular signaling, differentiation, migration, stemness,
autophagy, senescence, inflammation, immune response,
and cell death, apart from their long-standing role in energy
production. Additionally, mitochondria interact with each
other and with subcellular compartments such as the ER,
lysosomes, peroxisomes, endosomes, melanosomes, lipid
droplets, the plasma membrane, and the nuclear membrane
(reviewed by (Gordaliza‐Alaguero et al. 2019)). To effi-
ciently play these functions, mitochondria are constantly
adapting their morphology and localization in the cell, which
is collectively known as mitochondrial dynamics (Fig. 2).
As such, the mitochondrial network can range in shape from
isolated, rounded organelles to long interconnected tubules.
In addition, mitochondria can distribute evenly across the
cytosol or form clusters to meet local demands, events that
are cell specific and can vary throughout the cell cycle and
in response to metabolic and cellular clues (reviewed by
(Pernas and Scorrano, 2016)).
Mitochondrial dynamics is essential for maintenance of
health organelles as repeated cycles of organelle fusion and
fission are required for homogenization of the mitochondrial
network (Ban-Ishihara et al. 2013; Chen et al. 2003, 2005;
Ishihara et al. 2015; Twig et al. 2008). Furthermore, mito-
chondrial dynamics regulates organelle transport, inherit-
ance, and selective removal (Kleele et al. 2021; Lieber et al.
2019; Misko et al. 2012; Twig et al. 2008), with defects in
this machinery leading to a range of diseases in humans
(Table 1). Mitofusins 1 (MFN1) and 2 (MFN2) as well as
the optic atrophy protein 1 (OPA1), all belonging to the
dynamin-related family of large GTPases, are the main effec-
tors responsible for mitochondrial fusion in mammals (Chen
13
Biophysical Reviews
ER
MERCs
mitochondrial fusion
fusion
fission
elongated fragmented
mitochondria mitochondria
mitochondrial fission
MFN2
MFN1 cristae
OPA1
DRP1
matrix
ER
Fig. 2  Main effectors of mitochondrial dynamics. Cyclic events of
organelle fusion and fission (division) driving, respectively, elonga-
tion and fragmentation of the mitochondrial network are responsible
for determining mitochondrial dynamics. Towards that, mitofusins 1
(MFN1) and 2 (MFN2) as well as the optic atrophy protein 1 (OPA1)
are the main effectors of fusion. MFN1 and MFN2 are both located
in the outer mitochondrial membrane, whereas OPA1 resides in the
inner mitochondrial membrane. While MFN1 and OPA1 have a cen-
tral role in the fusion reaction, MFN2 is a key regulator of the oxi-
dative metabolism and has been implicated on mitochondria-endo-
plasmic reticulum (ER) contact sites (MERCs) formation. OPA1 is
also central to mitochondrial cristae remodeling. In turn, mitochon-
drial fission is primarily carried out by the dynamin-related protein
1 (DRP1), which locates in the cytosol and acts at sites of mitochon-
dria-ER membrane juxtaposition
et al. 2003, 2005, 2007, 2010). MFN1 and MFN2 are both
located in the outer mitochondrial membrane, whereas OPA1
resides in the inner mitochondrial membrane (Fig. 2). While
MFN1 and OPA1 have a central role in the fusion reaction,
the exact role of MFN2 in fusion remains unclear. OPA1
is also central to mitochondrial cristae remodeling, being
its function under the control of multiple enzymes such as
YME1L1, OMA1, and PARL (reviewed by (Pernas and
Scorrano, 2016)). More recently, mitoguardins 1 (MIGA1)
and 2 (MIGA1), which act downstream of mitofusins, have
also been shown to regulate mitochondrial fusion by inter-
acting with mitochondrial phospholipase D (MitoPLD) to
 Table 1  Main effectors of mitochondrial dynamics and their role in diseases
Gene
Mitofusin 1 (MFN1)
Mitofusin 2 (MFN2)
Optic atrophy 1 protein (OPA1)
Yeast mitochondrial escape 1-like 1
(YME1L1)
OMA1 zinc metalloprotease
Rbd1p orthologue presenilin-associated
rhomboid-like protein (PARL)
Dynamin-related protein 1 (DRP1)
Mitochondrial fission factor (MFF)
Mitochondrial fission 1 protein (FIS1)
Mitochondrial dynamics protein of 49 kDa
(MID49)
Mitochondrial dynamics protein of 51 kDa
(MID51)
13
Main role
Outer mitochondrial membrane protein that
mediates mitochondrial fusion
Outer mitochondrial membrane protein that
mediates mitochondrion-mitochondrion
interaction and juxtaposition of mitochon-
dria with the endoplasmic reticulum
Inner mitochondrial membrane protein that
mediates mitochondrial fusion
Inner mitochondrial membrane peptidase that
mediates OPA1 processing
Inner mitochondrial membrane peptidase that
mediates OPA1 processing
Inner mitochondrial membrane peptidase that
mediates OPA1 processing
Cytoplasmic protein that mediates mitochon-
drial fission
Outer mitochondrial membrane receptor that
recruits DRP1 for organelle fission
Outer mitochondrial membrane receptor that
recruits DRP1 for organelle fission
Outer mitochondrial membrane receptor that
recruits DRP1 for organelle fission
Outer mitochondrial membrane receptor that
recruits DRP1 for promoting organelle fis-
sion
Disease/symptoms
Unknown
Charcot-Marie-Tooth disease type 2A
(CMTD2A)
Hereditary motor and sensory neuropathy
(HMSN)
Multiple symmetric lipomatosis (MSL)
Canine fetal-onset neuroaxonal dystrophy
Autosomal dominant optic atrophy (ADOA)
Mitochondrial DNA depletion syndrome
Behr syndrome
Syndromic Parkinson disease and dementia
Intellectual disability, motor development
delay, expressive speech delay, optic nerve
atrophy associated with visual impairment,
and hearing impairment
Unknown
Unknown
Encephalopathy
Autosomal dominant optic atrophy
Microcephaly and pain insensitivity
Intractable forms of epilepsy
Neonatal lethality
Leigh-like encephalopathy, optic atrophy, and
peripheral neuropathy
Encephalopathy due to defective mitochon-
drial and peroxisomal fission
Unknown
Unknown
Unknown
References
Biophysical Reviews
Chen et al. (2003); Chen et al. (2005); Chen
et al. (2007); Chen et al. (2010)
Brockman et al. (2008); Chen et al. (2003);
Chen et al. (2007); Chen et al. (2005); Chen
et al. (2010); Fyfe et al. (2011); Rouzier
et al. (2012); Sawyer et al. (2015); Zhu et al.
(2005); Züchner et al. (2004)
Alexander et al. (2000); Amati-Bonneau et al.
(2008); Carelli et al. (2015); Delettre et al.
(2000); Hudson et al. (2008); Schaaf et al.
(2011); Spiegel et al. (2016)
Anand et al. (2014); Hartmann et al. (2016)
Anand et al. (2014)
Saita et al. (2017)
Fahrner et al. (2016); Gerber et al. (2017);
Ishihara et al., (2009); Kleele et al., (2021);
Losón et al. (2013); Sheffer et al. (2016);
Vanstone et al. (2016); von Spiczak et al.
(2017); Waterham et al. (2007)
Kleele et al., (2021); Koch et al. (2016); Losón
et al. (2013); Palmer et al. (2013); Shamseldin
et al. (2012)
Kleele et al., (2021); Losón et al. (2013);
Palmer et al. (2013); Shen et al. (2014);
Losón et al. (2013); Palmer et al. (2013)
Losón et al. (2013); Palmer et al. (2013)

facilitate MitoPLD dimer formation (Zhang et al. 2016a).
On other hand, mitochondrial fission is primarily carried out
by the dynamin-related protein 1 (DRP1), which locates in
the cytosol and is attracted to the mitochondrial outer mem-
brane by receptors such as the mitochondrial fission factor
(MFF), the mitochondrial fission 1 protein (FIS1), and the
mitochondrial dynamics proteins of 49 kDa (MID49) and
51 kDa (MID51). Once bound to these receptors, DRP1 is
capable of oligomerizing and driving mitochondrial division
(Fig. 2) (Giacomello et al. 2020; Ishihara et al. 2009; Kleele
et al. 2021).
Prior to mitochondrial fission, the smooth ER wraps
around mitochondria to possibly drive, with the aid of
actin filaments, initial organelle constriction (Fig. 2). Actin
polymerization further supports DRP1 oligomerization and
GTP hydrolysis-mediated membrane constriction (Chakra-
barti et al. 2018; Korobova et al. 2013; Manor et al. 2015).
It is noteworthy that MFF and DRP1 often colocalizes with
nucleoids, thus favoring maintenance of small and frag-
mented nucleoids, cristae structure, and the pro-apoptotic
status of mitochondria (Ban-Ishihara et al. 2013; Lewis
et al. 2016). Mitochondria-ER contact sites (MERCs) serve,
therefore, as fission platforms, apart from acting as impor-
tant hubs for lipid trafficking, ­Ca2+ signaling, ER stress,
apoptosis, and macroautophagy. Several protein complexes
such as VAPB-PTPIP51, IP3R1/2/3-GRP75-VDAC1, and
BAP31-FIS1 have been implicated in mitochondria-ER jux-
taposition. The same holds true for MFN2 (Fig. 2), which is
also present in the ER membrane where from it can homo-
oligomerize and hetero-oligomerize with either MFN2 or
MFN1 in mitochondria to tether both organelle membranes
(de Brito and Scorrano, 2008; Gordaliza‐Alaguero et al.
2019).
Regulation of mitochondrial dynamics
in oocytes and implications to fertility
Given that oocyte mitochondria have a fragmented morphol-
ogy, are vacuolated, and contain arched and concentrically
arranged cristae, it is tempting to suppose that these char-
acteristics are coordinated by specific regulation of mito-
chondrial dynamics in oocytes. To investigate this, Udagawa
et al. (2014) performed oocyte-specific deletion of DRP1 in
mice, finding that oocyte mitochondria are fusion compe-
tent as fission deficiency resulted in elongated organelles
(Fig. 3a). This conclusion is further supported by the pres-
ence of profusion proteins MFN1, MFN2, and OPA1 in
oocytes (Liu et al. 2016a; Wakai et al. 2014). Yet, overex-
pression of either MFN1 or MFN2 did not lead to mitochon-
drial tubulation (Wakai et al. 2014), supporting in oocytes
an imbalance of mitochondrial dynamics towards fission.
Alternatively, this result might be attributed to the short
13
Biophysical Reviews
period (≤ 15 h) of mitofusin overexpression or restricted to
late stages of oogenesis as mitochondrion-mitochondrion
contact sites were clearly increased following mitofusin
overexpression (Wakai et al. 2014). In addition, mitofusin
overexpression led to markedly aggregated mitochondria,
particularly around the nucleus/chromosomes (Wakai et al.
2014), a phenotype that relied on MFN1 GTPase activity and
associated with disrupted spindle/metaphase plate organiza-
tion (Wakai et al. 2014).
Targeted deletion of DRP1 during oocyte development
resulted in female infertility due to impaired folliculogen-
esis, a result attributed to depleted ER C­ a2+ stores, multio-
rganelle (i.e., mitochondria, ER, peroxisomes and vesicles)
aggregation, and defective secretory vesicle release (Fig. 3a)
(Udagawa et al. 2014). Curiously, neither mitochondrial
membrane potential nor mtDNA copy number was altered
in DRP1-deficient oocytes, although nucleoids were highly
clustered (Udagawa et al. 2014). The apparent lack of effect
on mitochondrial function contrasts with reports showing
that fission is critical for mitochondrial network homogeni-
zation and turnover (Ban-Ishihara et al. 2013; Ishihara et al.
2015; Ota et al. 2020; Twig et al. 2008), a finding that might
be secondary to the unique characteristics of mitochondria
in oocytes. In turn, targeted deletion of MFN1 strongly pre-
vented mtDNA accumulation during oocyte growth as well
as led to evident mitochondrial dysfunction characterized by
organelle swelling, abnormal expression of OXPHOS subu-
nits, decreased membrane potential, increased FAD level,
increased ROS level, and decreased ATP content (Fig. 3b).
MFN1-deficient oocytes also contained highly clustered
mitochondria with severe ultrastructure abnormalities such
as inner membrane vesicles and decreased number of cristae
(Carvalho et al. 2020; Hou et al. 2019; Zhang et al. 2019a).
These findings are consistent with previous reports show-
ing that MFN1 is required for mitochondrial health, mtDNA
stability, and OPA1 activity (Chen et al. 2003, 2005, 2007,
2010; Cipolat et al. 2004), thus confirming the important
role of fusion in oocytes as evidenced for MIGA1 and
MIGA2 knockouts (Liu et al. 2016b). Nonetheless, neither
MFN1 deficiency nor DRP1 overexpression enhanced mito-
chondrial fragmentation (Carvalho et al. 2020; Hou et al.
2019; Wakai et al. 2014; Zhang et al. 2019a), indicating
that mitochondrial size is strictly regulated in oocytes. This
finding contrasts, however, with that of oocytes lacking
the mitochondrial unfolded protein response CLPP, which
did display smaller mitochondria in addition to decreased
expression of profusion genes Mfn1, Mfn2, and Opa1 (Wang
et al. 2018a).
Apart from an evident mitochondrial dysfunction, MFN1-
deficient oocytes also presented increased apoptosis, disrup-
tion of adherens/gap junctions, and impaired communication
with granulosa cells (Fig. 3b) (Carvalho et al. 2020; Zhang
et al. 2019a). Remarkably, females with MFN1-deficient
Biophysical Reviews

a b MFN1 knockout
DRP1 knockout
mitochondrial
elongation
mitochondrial vesicles
dysfunction
mtDNA

ROS

Ca2+

ER
apoptosis PI3K-Akt ATP
multiorganelle secretory vesicle signaling
aggregation release

granulosa cell- granulosa cell-

oocyte communication oocyte communication

folliculogenesis folliculogenesis
fertility fertility

c MFN2 knockout Offspring

defective insulin
signaling
ATP

943 DEGs
slight liver
ER function increased
mitochondrial
phagosome insulinemia
dysfunciton
endocrine resistance
mitophagy

ER
glucose
mitochondrial increased intolerance
dysfunction weight gain
dysregulated
MERCs

Fig. 3  Mitochondrial dynamics in oocytes is essential to fertility
and links mitochondrial-endoplasmic reticulum (ER) dysfunction
with metabolic disorder transmission. Oocyte-specific deletion of
dynamin-related protein 1 (DRP1) results in oocytes with elongated
mitochondria, depleted endoplasmic reticulum (ER) calcium ­(Ca2+)
stores, multiorganelle (i.e., mitochondria, ER, peroxisomes and vesi-
cles) aggregation, and defective secretory vesicle release (a). In turn,
mitofusin 1 (MFN1) knockout strongly impairs mitochondrial dynam-
ics as evidenced by organelle swelling, clustering, abnormal cristae,
and inner membrane vesiculation, although mitochondrial shape
remains unchanged (b). These defects are paralleled by decreased
expression of oxidative phosphorylation subunits, decreased mito-
chondrial membrane potential, decreased mitochondrial DNA
(mtDNA) copy number, increased flavin adenine dinucleotide (FAD)
levels, and increased ROS levels. As a result, MFN1-deficient oocytes
have decreased ATP content, increased apoptosis, and impaired PI3K-
AKT signaling. Despite these differences, the lack of either MFN1 or
DRP1 results in infertility due impaired granulosa cell-oocyte com-
munication and arrested folliculogenesis. On the other hand, oocytes
lacking mitofusin 2 (MFN2) have a pronounced transcriptomic
change with 943 differentially expressed genes (DEGs) associated
with pathways regulating, among others, ER function, the phago-
some, endocrine resistance, and mitophagy (c). These oocytes also
present dysregulated mitochondria-ER contact sites (MERCs) and
mitochondrial dysfunction characterized by mitochondrial aggrega-
tion and swelling, decreased mitochondrial membrane potential,
lower mtDNA copy number, lower nicotinamide adenine dinucleotide
(phosphate) (NAD(P)H) levels, increased FAD levels, and decreased
ATP content. Unexpectedly, cristae structure is well developed in
MFN2-knockout oocytes, better than in wild-type mice. As a result,
oocyte-specific MFN2 deficiency results in offspring with increased
weight gain and glucose intolerance, abnormalities that associate with
slight liver mitochondrial dysfunction, increased insulinemia, and
impaired insulin signaling

oocytes never ovulated due to a folliculogenesis arrest at depletion (Carvalho et al. 2020; Hou et al. 2019; Zhang
the secondary-to-antral follicular stage, a phenotype that was et al. 2019a). Zhang et al. (2019a) associated these effects
shown to worsen with aging and led to accelerated follicular of MFN1 deletion to accumulation of ceramide in oocytes,

13

a membrane sphingolipid and an important inducer of apop-
tosis and cell cycle arrest (Fig. 3b). In turn, Carvalho et al.
(2020) found that the additional knockout of MFN2 miti-
gated the impact of MFN1 deficiency on folliculogenesis,
enabling enhanced mitochondrial health, oocyte growth, and
ovulation in double-knockout females (Carvalho et al. 2020).
Moreover, while the single loss of MFN1 altered the expres-
sion of 161 genes, the double loss of MFN1 and MFN2
impacted the expression of 474 genes when compared to
wild-type oocytes. Enrichment analysis of transcriptomic
differences linked the effects of single MFN1 deletion to
disrupted PI3K-Akt signaling (Fig. 3b), a pathway that
is known to have a fundamental role in oogenesis, being
required for granulosa cell-oocyte communication (Dong
et al. 1996; Liu et al. 2014; Reddy et al. 2008). In keeping
with this, previous reports have shown that MFN2 inhibits
the PI3K-AKT signaling (Chen et al. 2004, 2014; de Brito
and Scorrano, 2009; Ma et al. 2015b), suggesting that the
phenotype of MFN1-knockout oocytes may be explained,
at least in part, by a deleterious action of MFN2. Indeed,
Mfn1 expression in wild-type oocytes was fivefold higher
than that of Mfn2, and the treatment of MFN1-deficient
oocytes with an agonist of the PI3K-AKT signaling partially
rescued oogenesis/folliculogenesis (Carvalho et al. 2020).
Therefore, mitofusins seem to play distinct, nonredundant
roles in oocytes, with MFN1 acting downstream of MFN2
to counter its activity.
Role of mitochondrial dynamics
in oocyte‑linked transmission of metabolic
disorders
Although environmental and genetic factors are the main
determinants of metabolic disorders, female over-nutrition
permanently programs the metabolism of offspring (Agar-
wal et al. 2018; Akamine et al. 2010; Jungheim et al. 2010;
Mdaki et al. 2016; Murrin et al. 2012; Oestreich and Moley
2017; Rattanatray et al. 2010; Reynolds et al. 2013; Ruager-
Martin et al. 2010; Shankar et al. 2008; Wyman et al. 2008).
Accordingly, maternal obesity has been found to cause lipid
accumulation in granulosa cells and oocytes, thereby result-
ing in oocytes with dysfunctional mitochondria as evidenced
by their ultrastructural defects, aggregation, lower membrane
potential, increased ROS, and increased C ­ a2+ (Andreas et al.
2019; Boots et al. 2016; Boudoures et al. 2017; Ferey et al.
2019; Marei et al. 2020; Reynolds et al. 2013; Wu et al.
2010, 2015). In addition, obesity leads to MERC disruption,
ER stress, and activation of the unfolded protein response
(UPR) in oocytes (Marei et al. 2019, 2020; Wu et al. 2015;
Zhao et al. 2017). Thus, besides impacting oocyte health
and fertility, these abnormalities, likely underpinned by
abnormal mitochondria and epigenetic marks (Agarwal et al.
13
Biophysical Reviews
2018; Keleher et al. 2018; Ou et al. 2019; Ruebel et al. 2017;
Sirard, 2019; Wang et al. 2018b), can be passed down the
maternal lineage and contribute with the onset of metabolic
disorders in the following generations.
It is currently unclear the precise mechanism by which
obesity affects mitochondria and the ER in oocytes. How-
ever, it is well known that nutrient abundance can overload
the ETC with highly charged electrons, resulting in exces-
sive ROS generation and, eventually, oxidative stress. ROS
can damage mitochondria, leading to mitochondrial frag-
mentation and dysfunction, further aggravating the oxida-
tive stress (reviewed by (Kakimoto and Kowaltowski, 2016;
Zorzano et al. 2015)). In this context, MFN2 has been shown
to exert an important role in adapting the mitochondrial
metabolism according to nutrient availability. MFN2 acts
through regulation of both mitochondrion-mitochondrion
and mitochondrion-ER interactions, besides determining
mitochondrial interaction with other subcellular compart-
ments such as lipid droplets and lysosomes (reviewed by
(Benador et al. 2019; Gordaliza‐Alaguero et al. 2019)).
There is also a bunch of evidence connecting decreased
MFN2 expression with metabolic inflexibility, mitochon-
drial dysfunction, ER stress, impaired insulin signaling,
leptin resistance, glucose intolerance, obesity, and diabetes
(Bach et al. 2003; Mahdaviani et al. 2017; Mourier et al.
2015; Muñoz et al. 2014; Ngoh et al. 2012; Pich et al. 2005;
Schneeberger et al. 2013; Sebastian et al. 2012; Sebastián
et al. 2016; Tubbs et al. 2014).
Given the key role of MFN2 in regulating the energetic
metabolism, Garcia et al. (2020) have investigated whether
mouse dams with oocyte-specific deletion of MFN2 deliver
offspring that are prone to metabolic disorders. Earlier
reports have shown that MFN2 is not essential for oocyte
development, with little, if any, impact on fertility (Carvalho
et al. 2020; Hou et al. 2019; Zhang et al. 2019b). In spite
of this, MFN2-deficient oocytes displayed mitochondrial
dysfunction, dysregulated MERCs, and an overt transcrip-
tomic change encompassing 943 differentially expressed
genes (Garcia et al. 2020). Enrichment analysis of the tran-
scriptomic data revealed an over-representation of genes
related to ER function, phagosome, endocrine resistance,
and mitophagy (Garcia et al. 2020). These findings are in
keeping with previous reports in which MFN2 was targeted
through either oocyte-specific deletion or RNA interference,
thereby leading to mitochondrial dysfunction, shortened
telomeres, increased apoptosis, and, in turn, poor qual-
ity oocytes and accelerated follicular depletion (Liu et al.
2016a; Zhang et al. 2016b, 2019b). Likewise, MFN2 overex-
pression, which increased mitochondria-ER juxtaposition in
oocytes, led to alterations in the ER such as a disintegrated
­ a2+ stores (Wakai et al.
network, clusterization, and loss of C
2014). Consequently, offspring derived from MFN2-defi-
cient oocytes presented increased weight gain and glucose
Biophysical Reviews
intolerance, a phenotype that was linked to decreased insu-
linemia and defective insulin signaling (Garcia et al. 2020).
Accordingly, Zhao et al. (2017) have reported that obesity
affects MERCs in oocytes, an effect that is prevented by
PACS2 downregulation. Furthermore, Saben et al. (2016)
have shown that maternal metabolic syndrome leads to
persistent transmission of impaired mitochondrial fission
and decreased OPA1 expression across three generations.
Altogether, these findings support a role for mitochondrial
dynamics in regulating mother-to-offspring transmission of
metabolic disorders. Further studies should focus on charac-
terizing a possible underlying mechanism linking maternal
obesity with abnormal mitochondrial dynamics.
Concluding remarks
A large body of evidence supports that mitochondria are kept
under a relatively quiescent state in oocytes, likely to prevent
the gamete from oxidative stress once somatic granulosa
cells are responsible for supplying most of the energetic mol-
ecules needed for oogenesis. As such, mitochondrial health
is inextricably linked to mitochondrial dynamics, which
regulates in oocytes several aspects of the mitochondrial
biology including organelle morphofunctional characteris-
tics, mobility, interaction with subcellular compartments,
signal transduction, and apoptosis. Thereby, malfunctioning
of mitochondrial dynamics can disturb oocyte formation,
ultimately leading to infertility and disease transmission.
Acknowledgements Marcos R. Chiaratti is funded by the São Paulo
Research Foundation (FAPESP/Brazil – grants # 2017/04372-0 and
2020/15412-6), Conselho Nacional de Desenvolvimento Científico e
Tecnológico (CNPq/Brazil), the Coordenação de Aperfeiçoamento de
Pessoal de Nível Superior (CAPES/Brazil – finance code 001), and the
Academy of Medical Sciences-Newton Advanced Fellowship.
Declarations
Ethical approval This article does not contain any studies with human
participants or animals performed by the author.
Conflict of interest The author declares no competing interests.
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