ISSN 0006-2979, Biochemistry (Moscow), 2025, Vol. 90, No. 12, pp. 1957-1969 © Pleiades Publishing, Ltd., 2025.
Russian Text © The Author(s), 2025, published in Biokhimiya, 2025, Vol. 90, No. 12, pp. 2063-2076.
1957
Mitochondrial Reticulum in Skeletal Muscles:
Proven and Hypothetical Functions
Lora E. Bakeeva
1
, Valeriya B. Vays
1
, Irina M. Vangeli
1
,
Chupalav M. Eldarov
1,2
, Vasily A. Popkov
1
, Ljubava D. Zorova
1,2
,
Savva D. Zorov
1,3
, and Dmitry B. Zorov
1,2,a
*
1
Belozersky Research Institute of Physico-Chemical Biology, Lomonosov Moscow State University,
119991 Moscow, Russia
2
Kulakov National Medical Research Center of Obstetrics, Gynecology, and Perinatology;
Ministry of Health of the Russian Federation, 117997 Moscow, Russia
3
Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University,
119991 Moscow, Russia
a
e-mail: zorov@belozersky.msu.ru
Received July 8, 2025
Revised October 12, 2025
Accepted October 19, 2025
Abstract— The mitochondrial reticulum of skeletal muscles has been characterized in the 1970-80s. It has
been suggested and then proven its role is delivering energy in a form of transmembrane potential on the
mitochondrial inner membrane throughout the cell volume, followed by ATP synthesis by the mitochondrial
ATP synthase. However, the data on the mitochondrial ultrastructure still remains a subject to criticism.
Toexclude the possibility of artifacts caused by the sample preparation for electron microscopy, we compared
the structure of mitochondria in the ultrathin sections of muscle fibers observed by electron microscopy and
in intact fibers stained with a membrane potential-dependent dye and visualized by confocal microscopy.
Thecomparison was carried out for mice and naked mole rats known for their superior longevity. The obtained
results confirmed previous findings regarding the structure of mitochondrial reticulum. A model suggesting
the functioning of giant mitochondria as intracellular structures preventing tissue hypoxia was proposed.
DOI: 10.1134/S000629792560190X
Keywords: mitochondria, ultrastructure, reticulum, membrane potential, hypoxia, oxygen transport, mouse,
naked mole rat
* To whom correspondence should be addressed.
INTRODUCTION
According to the concepts established based on
the chemiosmotic theory by Peter Mitchell, mito-
chondrial energetics is determined by the intrami-
tochondrial coupling of the oxidation of respiratory
substrates and ATP generation [1-3]. The energy gen-
erated by the activity of mitochondrial proton pumps
(complexes I, III, and IV) is stored in two forms: the
difference in the hydrogen ion concentrations on
both sides of the inner mitochondrial membrane
(IMM) (ΔpH; the exterior being more acidic than the
matrix) and the difference in the electrical charges
in these compartments (negative charge of the ma-
trix side). This energy, in particular its electrical form
(ΔΨ), is used for the rotation of a portion of the ATP
synthase complex with the generation of ATP [4, 5].
Later, it was shown that mitochondria also use potas-
sium energetics, in which the transport of potassium
ions through the ATP synthase complex also controls
the synthesis of ATP [6-9]. The main component in
both types of mitochondrial energetics is the mito-
chondrial membrane potential created by the respi-
ratory chain [10].
The maintenance of the optimal balance be-
tween the energy production and expenditure is a
rather significant issue [11], especially under stress
conditions, which requires increased ATP production
BAKEEVA et al.1958
BIOCHEMISTRY (Moscow) Vol. 90 No. 12 2025
in order to adequately supply the entire cell volume
with oxidative substrates and oxygen and/or with ATP
to power endergonic reactions. The primary supplier
of oxygen and nutrient substrates is the circulatory
system that delivers them to tissues. An imbalance
created when the consumption of oxygen and sub-
strates exceeds their delivery to compartments locat-
ed downstream in the circulation system results in
ischemia/hypoxia. When a quick switch to glycolysis
is impossible (even if the efficiency of glycolysis as
an energy-producing mechanism is low), both hypox-
ia and ischemia can have fatal consequences. This
imbalance can be avoided by reducing the depen-
dence on the oxidative energy sources, i.e., by de-
livering ATP evenly throughout the tissue. There are
several possible scenarios providing an adequate ATP
supply to the entire cellular volume. In one of them,
ATP is produced by the mitochondria located near
the source of oxygen and oxidation substrates (blood
capillaries), after which it diffuses into the tissue.
However, this diffusion is limited by the existence
of various intracellular protein and lipid structures
that act as a barrier to ATP diffusion, which prevents
the cells from maintaining a balance between the
energy intake and expenditure within the entire cell
volume, especially under stress conditions.
Another possibility for providing energy to all
cellular compartments can be realized if the cells lo-
cated between the blood capillaries are crossed by
a continuous, gap-free mitochondrial network with a
preferential location of proton pumps at the sourc-
es of substrates and oxygen and with a uniform dis-
tribution throughout the network of ATP synthase
complexes ready to provide ATP synthesis at any
moment. In this case, the network will be energized
by the activity of proton pumps located near the cap-
illaries, while ATP can be produced at any site within
the cell volume due to the uniform distribution of ΔΨ
(equipotentiality) along the entire length of the mito-
chondrial network. This second scenario, was theoret-
ically justified by V. P. Skulachev in 1969 for the IMM
and other coupling membranes (e.g., chloroplast and
bacterial ones) and allowed to formulate the theory
of coupling membranes as “electrical cables” used for
the rapid and efficient transfer of electrical energy
in the cell [12]. In particular, it was suggested that
IMMs act as intramitochondrial “electrical wires” for
providing an adequate supply of ATP to the cellular
volume.
It should be admitted that before the develop-
ment of mitochondria visualization methods using
fluorescent probes, the optical limitations of conven-
tional light microscopy together with a rapid devel-
opment of electron microscopy, had led to the loss
of the intuitive perception of the three-dimensional
structure of mitochondria based on two-dimensional
electron microscopy image. A significant progress has
been achieved when the scientists started to use seri-
al ultrathin sections for the three-dimensional recon-
struction of cells and most importantly, the mitochon-
dria. A breakthrough was the use of this approach
for the reconstruction of the mitochondrial network
in the diaphragm (striated) muscle, which revealed
that in rat diaphragm muscle fibers, the bulk of mi-
tochondrial material was located in a plane perpen-
dicular to the long axis of the muscle fiber, in the
isotropic zones on both sides of the Z-line in a form
of layers consisting of extended, branched mitochon-
dria. Accordingly, in each muscle fiber, the number
of such mitochondrial layers was equal to the num-
ber of Z-lines multiplied by two. All these numerous
layers were interconnected and formed a single mi-
tochondrial system represented by the vertical rows
of mitochondria running along the myofibrils. This
structure of the mitochondrial apparatus was named
the mitochondrial reticulum [13]. However, in the di-
aphragm muscles of rat embryos and neonatal rats,
the entire mitochondrial system was represented by
small, single, non-branching, elongated mitochon-
dria located along the myofibrils [14]. In 1978, com-
pelling arguments were obtained in support of the
theory of mitochondria functioning as intracellular
electrical cables. Based on the idea that IMMs act as
mitochondrial electrical cables extending over long
distances without breaks, it has been found that mi-
tochondrial branches contact through the osmiophilic
electron-dense junctions, while the IMMs themselves
do not form physical contacts with each other [13].
Such electron-dense junctions have been found in
abundance in rat cardiomyocytes, suggesting that the
mitochondrial reticulum in cardiac cells is formed by
multiple clusters of mitochondrial branches connect-
ed by the mitochondrial junctions [15].
In 1986-1988, the theory of mitochondria as elec-
trical cables has been experimentally confirmed, first,
for the filamentous mitochondria of fibroblasts and
then for the mitochondria of neonatal cardiomyocytes
formed by establishing the contacts between the mi-
tochondrial clusters [16, 17]. It was shown that local
deenergization of mitochondria led to the depolariza-
tion of the entire mitochondrial cluster, including its
connections formed by the junctions, thus indicating
the possibility of electrical communication between
the IMMs. It was suggested that the junctions can
be in the “on” or “off” state, depending on the need
for a certain size of the equipotential mitochondri-
al cluster. Several decades later, similar conclusions
were made when the three-dimensional organization
of striated muscle cells was assessed with modern
methods, using the concept of mitochondria as ex-
tended power plant [18, 19]. However, despite the ob-
tained evidence, there is still an occasional criticism
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BIOCHEMISTRY (Moscow) Vol. 90 No. 12 2025
of the methodology employed to assess the mitochon-
drial reticulum organization in skeletal muscles, most-
ly, of procedures used for the sample preparation in
electron microscopy. Hence, this required the use of
other methods, whose results could be compared with
the electron microscopy data. Such arguments have
become the basis for our study, in which we com-
pared the mitochondrial organization in vital skeletal
muscle sections observed by confocal microscopy with
the images obtained by conventional electron micros-
copy. The muscles were isolated from mice and naked
mole rats, as the latter have a superiorly long lifes-
pan associated, in part, with the structural and func-
tional characteristics of their mitochondria [20-23].
MATERIALS AND METHODS
Laboratory animals. Mice. Male 2.5-month-old
C57Bl/6 mice (n = 5) were housed in individually
ventilated cages (IVCs), with a 12/12 light/dark cycle
at 20-24°C with ad libitum access to food and water.
Safe BK 8/15 wood chips (JRS, Germany) were used
as bedding.
Naked mole rats (Heterocephalus glaber). Two
groups of naked mole rats (6-week- and 7-year-old)
were used in the experiments; each group contained
four animals. Given that the lifespan of a naked mole
rat is ~30 years, a 7-year-old animal is approximately
equivalent to a young mouse assuming that the mouse
lifespan is ~1.5-2 years. Naked mole rats were taken
from the colonies maintained in plexiglass mazes at
the Belozersky Institute of Physico-chemical Biology,
Lomonosov Moscow State University kept at 26–29°C
and relative humidity of 60-80%. Food was ad libitum
and included sweet potatoes, carrots, apples, fennel,
cereals with vitamins and minerals and oatmeal.
Visualization of muscle vital sections by con-
focal microscopy. Quadriceps femoris muscles were
collected from the animals anesthetized with 2.5%
isoflurane using a SomnoSuite® system (Kent Scien-
tific Corporation, USA) and sacrificed by decapitation.
The samples were placed in the incubation medium
(DMEM/F12 without sodium bicarbonate; PanEco,
Russia) to remove blood, after which they were em-
bedded in low-melting-point agarose (Thermo Fischer
Scientific, USA). Sections (70-100 μm thick) were pre-
pared with a Leica VT-1200s vibratome (Leica Bio-
systems, UK), washed with the incubation medium,
and incubated for 30 min with 200 nM tetramethyl-
rhodamine ethyl ester (TMRE), Thermo Fisher Scien-
tific). All procedures were performed at 25°C. Mito-
chondria in the TMRE-loaded muscle sections were
visualized using an LSM 710 inverted laser confocal
microscope (Carl Zeiss, Germany) with excitation at
543 nm and emission >560 nm.
Electron microscopy. Excised muscle tissue
samples were fixed with 3% glutaraldehyde (Sigma-
Aldrich, USA) in 0.1 M phosphate buffer (pH 7.4) for
2 h at 4°C and then with 1% osmium tetroxide for
1.5 h, dehydrated in a series of increasing ethanol
concentrations of 50, 60, 70, 80, and 96% (70% etha-
nol contained 1.4% uranyl acetate (Serva, Germany)
to enhance the contrast) and embedded in Epon812
epoxy resin. A series of sequential ultrathin sections
were prepared using a Leica ultramicrotome (Leica
Biosystems). Visualization was performed with a
JEM1400 electron microscope (JEOL, Japan) equipped
with a QUEMESA camera (Olympus, USA) at an accel-
erating voltage of 100 kV and beam current of 65 μA.
The images were processed using the software pro-
vided by the manufacturer (EMSIS GmbH, Germany).
RESULTS
Figure 1a shows an image taken from the skeletal
muscle fiber (m. quadriceps) section from a 3-month-
old mouse obtained by confocal microscopy. The sec-
tions were treated for 20-30 min with the ΔΨ-depen-
dent probe TMRE for 20-30min immediately after the
animal had been sacrificed, which made possible the
detection of energized mitochondria due to the differ-
ence in the mitochondrial fluorescence intensity rela-
tive to the cytoplasm. The use of the fluorescent dye
allowed to observe in real-time both the morphology
of the mitochondrial apparatus (all cellular structures
that fluoresced were mitochondria) and the level of
mitochondrial activity (the higher the TMRE fluores-
cence intensity, the higher the mitochondrial energi-
zation). The entire cross-sectional area of the muscle
fiber was packed with a dense network of branched,
energized mitochondria. The obtained image of the
mitochondrial system structure in live skeletal mus-
cle fibers fully corresponded to the ultrastructure of
the mitochondrial reticulum revealed by transmission
electron microscopy (Fig. 1b).
Using the same approach, we analyzed the struc-
ture of the mitochondrial apparatus in the skeletal
muscles (m. quadriceps) from naked mole rats aged
6 months and 7 years. Figure 2a shows that unlike
the muscle fibers of mice, the muscle cells of mole
rats lacked the mitochondrial network, and their mi-
tochondria are distributed rather randomly.
These data are fully consistent with the assump-
tion that the mitochondrial reticulum is absent in
skeletal muscle fiber of naked mole rat. Even by the
age of 7-11 years, when the organization of the mi-
tochondrial apparatus is permanently established,
it differs from that in mice [23]. It should be not-
ed once again that the lifespan of naked mole rats
reaches 30 years, and an animal at the age of 7-11
BAKEEVA et al.1960
BIOCHEMISTRY (Moscow) Vol. 90 No. 12 2025
Fig. 1. Comparison of the mitochondrial apparatus in the skeletal muscle fiber (m. quadriceps) of a 2.5-month-old mouse
revealed by confocal microscopy and transmission electron microscopy: a)confocal microscopy of a TMRE-loaded vital sec-
tion of skeletal muscle fiber; b)electron microscopic image of a fixed section through the muscle fiber. The mitochondrial
reticulum in panel b (dark profiles; arrows indicate mitochondrial elements of the reticulum) forms a single mitochondrial
network organized by the branched mitochondria occupying the entire sectional area of the muscle fiber, similar to that
revealed by confocal microscopy. Both images clearly demonstrate a developed network of the mitochondrial reticulum
formed by a system of thread-like extended mitochondria located in the isotropic region of the muscle fiber.
is approximately equivalent to a sexually mature
mouse, whose lifespan is ~1.5-2 years.
Therefore, the use of intact tissue and its examina-
tion immediately after sampling (i.e., without fixation,
dehydration, or freezing), allowed us to observe the
actual structure of the skeletal muscle mitochondrial
apparatus in a form of reticular (continuous) and non-
reticular (discontinuous) mitochondrial structures.
To obtain more a convincing and unambiguous
evidence of the absence of mitochondrial reticulum
in the skeletal muscles of naked mole rats, we an-
alyzed the mitochondrial profiles in a series of six
sequential ultrathin sections observed by electron mi-
croscopy (Fig. 3). Unlike in mice and rats, the mito-
chondrial structures in naked mole-rats did not form
a single network (reticulum), but were represented by
fragments that did not contact each other. This char-
acteristic mitochondrial organization was observed in
the muscle cells of both young (6-month-old) (Fig. 4)
and mature (7-year-old) animals.
DISCUSSION
The presence of a branched and morphologically
homogeneous mitochondrial network in rat striated
MITOCHONDRIAL RETICULUM IN SKELETAL MUSCLES 1961
BIOCHEMISTRY (Moscow) Vol. 90 No. 12 2025
Fig. 2. The structure of mitochondrial population in the skeletal muscle (m. quadriceps) of a 7-year-old naked mole rat:
a) confocal microscopy image of the muscle fiber vital cross-section showing the absence of mitochondrial network and
a chaotic distribution of individual mitochondria; b) transmission electron microscopy image of the cross-section through
the muscle fiber isotropic zone showing small single mitochondria (dark profiles indicated by arrows); c) enlarged image
of the fixed muscle fiber cross-section.
muscle was first described in 1978 [13] based on
analysis of electron microscopy images. However,
sample preparation for electron microscopy includes
fixation, staining, and dehydration steps, so there is
always a concern that these procedures may alter the
actual morphology existing in an intact tissue. There-
fore, it is advisable to confirm the electron microsco-
py data using other methods excluding the influence
BAKEEVA et al.1962
BIOCHEMISTRY (Moscow) Vol. 90 No. 12 2025
Fig. 3. Ultrathin serial sections (a-f) of a skeletal muscle fiber isotropic region from a 7-year-old naked mole rat contain-
ing single, small, unbranched mitochondria that do not form a mitochondrial reticulum. Section thickness, ~700-900 Å;
total thickness of the examined portion of the fiber, ~5 μm; arrow indicates the same mitochondrion in each image for
orientation along the sections.
of chemical agents used for sample fixation and of
other treatment procedures, including dehydration.
Another issue that requires consideration is
whether the mechanism of structural unification
of mitochondria into a single network is universal.
It is obvious that the formation of such mitochondrial
network can be advantageous if it leads to a more or
less uniform delivery to cellular compartments of the
membrane potential formed in the mitochondria, ATP,
heat, reactive oxygen species (ROS), and products
of mitochondrial synthesis (e.g., steroid hormones),
as well as removal of nitrogen metabolites through
the synthesis of urea and implementation of other,
non-energetic functions [24]. On the other hand, such
unification of mitochondria is possible only under
conditions that are “comfortable” for the cell, because
even a local disruption in the mitochondrial structure
integrity can lead to the energetic death of entire mi-
tochondrial system [16, 17]. Therefore, the fragmenta-
tion of mitochondrial reticulum may be more rational
under the action of pathogenic factors [25-31]. In this
case, even if individual components of the mitochon-
drial reticulum are damaged, there is a chance for the
network restoration due to proliferation of undam-
aged elements after removal of the deleterious factor.
Here, we demonstrated that in the skeletal muscle of
naked mole rat, the mitochondrial structure is repre-
sented by individual mitochondria, while in the same
muscles of mice and rats, the mitochondria form a
reticular structure. Moreover, this unification of mi-
tochondria occurs at the early stages of postnatal
development, since no mitochondrial reticulum was
detected in the muscles of rat embryos and newborn
pups [14]. In naked mole rats, the mitochondrial pop-
ulation is represented by individual mitochondria at
all studied stages of postnatal development [23]. This
is consistent with the concept proposed by V. P. Sku-
lachev on the neoteny as a characteristic feature of
naked mole rats [32]. In any case, with the reticulum
fragmentation, all possible hypothetical advantages
MITOCHONDRIAL RETICULUM IN SKELETAL MUSCLES 1963
BIOCHEMISTRY (Moscow) Vol. 90 No. 12 2025
Fig. 4. Electron microscopy image taken from the ultrathin section of quadriceps femoris of a 6-month-old naked mole rat.
of cooperation of individual mitochondria disappear,
as well as the danger of simultaneous damage to the
entire mitochondrial population. Such danger may
arise due to the unexpectedly high levels of oxida-
tive stress observed in the tissues of naked mole rats
[33-35]. It is known that the process of fragmenta-
tion (fission) of mitochondria occurs primarily under
conditions of increased ROS generation [31]. However,
the differences in the three-dimensional organization
of the mitochondrial population do not exclude the
possibility of mitochondria performing vital functions
not associated with energetic functions [24].
It is generally accepted that the primary function
of mitochondria is energy production; mitochondria
are one of the key elements in maintaining the bal-
ance between the expenditure and production energy
in the cells. A disruption of this balance leads to the
energy crisis and can be fatal for any cell, organ, or
organism [11].
Another function of mitochondria, which for a
long time had remain unobvious, is adjustment of
their three-dimensional structure and ultrastructure
to the cell’s immediate needs, which have led to the
emergence of the term “mitochondrial morphofunc-
tion” [36]. The use of modern microscopy methods
has made it possible to describe in detail the struc-
tural elements of mitochondria and their dynamics,
which have been linked to the functional character-
istics of these organelles [37].
Early attempts to find the associations between
the functional states of mitochondria in vitro (pro-
posed by Chance and Williams [38, 39]) and their
structure resulted in the description of different
structural states, such as orthodox, twisted, swollen,
and condensed [40-45]. However, very few studies at-
tempted to find this correspondence for the in situ
or in vivo results [46, 47]. Later, these studies were
criticized; in particular, the critics required to re-eval-
uate the IMM architecture based on the data obtained
by methods other than electron microscopy [48-50].
A comprehensive description of changes in the in-
ternal structure of mitochondria and its response to
various challenges needs more time. However, such
studies can be significantly hindered by the hetero-
geneity of the three-dimensional structure and ultra-
structure of mitochondria [51-55], together with the
proven functional specialization of the mitochondrial
population members in the cell [56]. The heteroge-
neity and specialization of mitochondria are even
more complicated by the contribution of mitochon-
drial quality control [57], whose integral elements are
mitochondrial fusion and symmetric and asymmetric
fission [25-31]. Visually detectable disruptions of the
mitochondrial structure can be a significant indica-
tor of the mitochondrial state and indicate profound
changes in the mitochondrial functioning, including
formation of pathological cell phenotypes. In this
case, the energy production aspect may recede into
BAKEEVA et al.1964
BIOCHEMISTRY (Moscow) Vol. 90 No. 12 2025
Fig. 5. Proposed model of the influence of muscle cell mitochondrial reticulum on the redox potential and oxygen partial
pressure (pO
2
) across the tissue. a) Less steep oxygen gradient along the distance from the blood capillary (limited by
red lines) when the mitochondrial reticulum is organized as a continuous mitochondrial tree (upper part) or chains of
mitochondria connected into an equipotential unit by electrically permeable inter-mitochondrial junctions (lower part;
junctions are shown in pink). The value of the membrane potential value in the mitochondrial matrix (dark green color
in all mitochondria) is the same over all mitochondrial chain. b)Steeper oxygen gradient when the mitochondrial tree has
been broken into fragments or in the absence of electrical communication between the mitochondria connected end to
end. The changes in color from yellow to red with the increasing distance from the capillary indicate the degree of tissue
oxygenation. The values of mitochondrial membrane potential are directly proportional to the intensity of green color in
the mitochondrial matrix; c-e) Krogh’s model describing changes in pO
2
in muscle tissue during physical exercise in the
case of the giant mitochondrion functioning as an oxygen supplier (c) and in its inability in the case of mitochondrial
fragmentation (d). Panel d shows the superposition of the two models for a qualitative representation of the volumetric
advantage (indicated by the shaded area), i.e., an increase in the volume fraction of normoxic tissue and decrease in the
oxygen gradient in the longitudinal and transverse directions relative to the capillary. Rt, radius of tissue with pO
2
values
not limiting the rate of tissue respiration; Rc, radius of the capillary; Rn, radius of normoxic tissue along the length of
the capillary. The direction of blood flow is shown with a downward arrow
the background and reflect changes in the function-
ing of mitochondria as important source of alterna-
tive non-energetic functions [24].
Despite all these problems, the existence of a
three-dimensional mitochondrial structure ranging
from single rounded and small fragments to exten-
sive branched mitochondrial networks, has been ful-
ly proven [58-67]. It should be noted that the mito-
chondrial reticulum in a form of extended and often
branched structures is characteristic of cells under
relatively comfortable conditions. In these cells, en-
ergy expenditure is initially high or can increase
acutely depending on the situation. This is what ex-
plains the existence of a single, complexly organized
mitochondrial reticulum in muscle cells, which are
distinguished by their high metabolism and ability to
mobilize in response to incoming challenges. In this
regard, the organization of mitochondria in muscle
tissue differs from that in other cells, where mito-
chondria sometimes form a network that breaks into
fragments under unfavorable conditions. No visually
similar fragmentation of the mitochondrial reticu-
lum in muscle cells has been demonstrated, although
based on the presence in the muscle mitochondria
of proteins responsible for the mitochondrial fission
and fusion (e.g., fis-1, drp1, Mfn2 [68, 69]) it has been
claimed that it also happens in these cells. The chang-
es in the three-dimensional organization of mito-
chondria from individual mitochondrial filaments to
a widely branched mitochondrial network filling the
entire cell volume in the ontogenesis were observed
only for the diaphragm muscle [13, 14]. An important
element in the organization of this network in ma-
ture muscle cells is intermitochondrial junctions [15],
which can be electrically conductive [17] and, pre-
sumably, can be in the “off” position, although this
remains to be proven. However, it can be assumed
that transmission of electrical signal through the mi-
tochondria over a distance can be blocked by the
fragmentation of the mitochondrial reticulum, e.g.,
through the rupture of existing intermitochondrial
junctions [28, 31]. Our study proves the existence of
an extended mitochondrial reticulum in muscle cells
based on a comparison of data obtained by two dif-
ferent methods (electron and laser confocal micros-
copies) and demonstrates the variability of mitochon-
drial reticulum in the same type of cells in animals
belonging to the same group (rodents).
MITOCHONDRIAL RETICULUM IN SKELETAL MUSCLES 1965
BIOCHEMISTRY (Moscow) Vol. 90 No. 12 2025
In a recent publication [70], we hypothesized
that the mitochondrial reticulum has functions other
than acting as an electrical cable [70]. We proposed
that the presence of a single equipotential mitochon-
drial network significantly equalizes both the redox
potential and energy availability to cellular compart-
ments throughout the cell. This might be the case at
the steady-state levels of energy intake and utilization
in the absence of oxidative stress. However, in the
presence of oxidative stress, mitochondria can break
apart, and each mitochondrial fragment can have its
own redox environment. The relationship between
the potential on the IMM and redox potential can be
quite complex due to the fact that the overall redox
potential in the tissue will be in equilibrium with the
mitochondrial NADH/NAD ratio, which should theo-
retically be high in a tissue hypoxic region (because
of the absence of respiration and resulting NAD re-
duction). However, hypoxia can lead to the increased
ROS generation with the possibility of ROS-induced
ROS release in some mitochondria with a depleted
redox buffer [71-73]. As a result, cells in potentially
hypoxic tissue regions can have a highly heteroge-
neous pattern of membrane potential values in in-
dividual mitochondrial fragments and different re-
dox potential values around them. This picture may
change if we assume the role of giant mitochondria
as oxygen conductors. The main argument in favor
of this assumption is a higher solubility of oxygen
in the lipid environment compared to the aqueous
medium surrounding the phospholipid membranes.
The continuity of phospholipid membranes, which is
observed in the case of extensive branching of the
mitochondrial network, can provide oxygen delivery
throughout the tissue volume. This continuum can
also be extended to the organization of the entire
mitochondrial reticulum by combining individual mi-
tochondrial clusters via intermitochondrial contacts,
which is typical for striated muscles, in particular,
cardiomyocytes [13-15, 17]. Considering a high os-
miophilicity (lipophilicity) of mitochondrial junctions,
one can also assume the possibility of high oxygen
solubility in these contacts, leading to a relative con-
tinuum of oxygen content throughout the mitochon-
drial network. Figure 5 presents a model explaining
a possible role of a giant mitochondrial network as
an intracellular system enabling an anti-hypoxic de-
fense. An important component of this model is the
previously discussed Krogh cylinder model [74] that
allows to calculate the possibility of existence of a
hypoxic tissue volume when moving deeper into the
tissue and along the flow from the blood capillary de-
livering oxygen [75, 76]. If a mitochondrial network
can serve as an oxygen carrier, this will allow the
tissues (especially those under heavy loads, for exam-
ple, during active muscular work) to have an oxygen
gradient that would be less steep compared to that
in the tissue containing a network disintegrated into
individual mitochondria. Of course, this model needs
experimental support.
CONCLUSION
The presence of mitochondrial reticulum in skel-
etal muscle can be considered proven. The three-di-
mensionality of this reticulum is achieved by the
connection of individual mitochondria by electrical-
ly permeable junctions throughout the cell’s volume,
which allows the mitochondrial structure to com-
pletely encompass the entire volume of muscle cell.
Given a high metabolic activity of the working mus-
cle, this reticulum-like organization of mitochondria
likely better meets the metabolic demands. Based on
this reasoning, it was hypothesized that the electri-
cal activity of mitochondria could support these de-
mands due to the potential equipotentiality of the
mitochondrial network, ensuring uniform energy de-
livery to all cellular compartments. The experimental-
ly confirmed concept of the mitochondrial reticulum
functioning as a branched electrical cable is comple-
mented by the hypothesis that this reticulum can also
ensure a uniform distribution of the redox potential
and molecular oxygen throughout the cell. This may
be an important factor in the cell metabolic homeo-
stasis, in which mitochondria play a key role.
Abbreviations
IMM inner mitochondrial membrane
ROS reactive oxygen species
TMRE tetramethylrhodamine ethyl ester
Contributions
L.E.B. supervised electron microscopy studies; V.B.W.,
I.M.V., and Ch.M.E. conducted electron microscopy
studies; V.A.P. performed laser confocal microscope ex-
periments; L.D.Z. and S.D.Z. developed the antihypox-
ic model of extended mitochondria involvement and
edited the manuscript; D.B.Z. developed the concept,
supervised the study, and wrote the manuscript.
Funding
The study was supported by the State Assignment of
the Ministry of Health (no.124013000594-1) and State
Assignment to the Lomonosov Moscow State Universi-
ty (no.AAAA-A19-119031390114-5).
Ethics approval and consent to participate
All procedures involving animals complied with the
ethical standards of the institution where the research
was conducted and approved legal acts of the Russian
Federation and international organizations. Animal
BAKEEVA et al.1966
BIOCHEMISTRY (Moscow) Vol. 90 No. 12 2025
study protocols were reviewed and approved by the
Ethics Committee of the Belozersky Research Institute
of Physicochemical Biology in accordance with the
Federation of European Laboratory Animal Societies
(FELASA) guidelines.
Conflict of interest
The authors of this work declare that they have no
conflicts of interest.
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