Article

ISSN 0006-2979, Biochemistry (Moscow), 2023, Vol. 88, No. 10, pp. 1596-1607 © Pleiades Publishing, Ltd., 2023.

Published in Russian in Biokhimiya, 2023, Vol. 88, No. 10, pp. 1926-1939.

1596

REVIEW

Mitochondrial Network: Electric Cable and More

Polina A. Abramicheva

, Nadezda V. Andrianova

, Valentina A. Babenko

1,2

Ljubava D. Zorova

1,2

, Savva D. Zorov

1,3

, Irina B. Pevzner

1,2

, Vasily A. Popkov

1,2

Dmitry S. Semenovich

, Elmira I. Yakupova

, Denis N. Silachev

1,2

, Egor Y. Plotnikov

1,2

Gennady T. Sukhikh

, and Dmitry B. Zorov

1,2,a

Belozersky Research Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119991 Moscow, Russia

Kulakov National Medical Research Center of Obstetrics, Gynecology and Perinatology, 117997 Moscow, Russia

Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, 119991 Moscow, Russia

e-mail: zorov@belozersky.msu.ru

Received July 12, 2023

Revised September 20, 2023

Accepted September 22, 2023

Abstract— Mitochondria in a cell can unite and organize complex, extended structures that occupy the entire cellu-

lar volume, providing an equal supply with energy in the form of ATP synthesized in mitochondria. In accordance with

thechemiosmotic concept, the oxidation energy of respiratory substrates is largely stored in the form of an electrical poten-

tial difference on the inner membrane of mitochondria. The theory of the functioning of extended mitochondrial structures

as intracellular electrical wires suggests that mitochondria provide the fastest delivery of electrical energy through thecel-

lular volume, followed by the use of this energy for the synthesis of ATP, thereby accelerating the process of ATP delivery

compared to the rather slow diffusion of ATP in the cell. This analytical review gives the history of the cable theory, lists

unsolved critical problems, describes the restructuring of the mitochondrial network and the role of oxidative stress in this

process. In addition to the already proven functioning of extended mitochondrial structures as electrical cables, a number

of additional functions are proposed, in particular, the hypothesis is put forth that mitochondrial networks maintain

the redox potential in the cellular volume, which may vary depending on the physiological state, as a result of changes in

the three-dimensional organization of the mitochondrial network (fragmentation/fission–fusion). A number of patholo-

gies accompanied by a violation of the redox status and the participation of mitochondria in them are considered.

DOI: 10.1134/S0006297923100140

Keywords: mitochondria, reticulum, network, electricity, membrane potential, fragmentation, fission, cardiomyocytes,

spermatozoa, oxidative stress, redox, preeclampsia, fetal growth retardation

* To whom correspondence should be addressed.

MITCHELL’S CHEMIOSMOTIC CONCEPT.

RESOLVED AND UNRESOLVED ISSUES

Historically, in the sixties of the twentieth century,

there was a transition from a purely chemical concept of

oxidative phosphorylation to a chemiosmotic one, pro-

viding spatial separation and functional coupling of ox-

idation processes (which creates a protonmotive force)

and usage of this force for the phosphorylation of ADP,

and this concept became dominant in bioenergetics [1-3].

However, it should be noted that there are still disputes

on accuracy of terminology and on principles of cou-

pling. In the first case, it is not very clear how much

the term “osmotics” is relevant to this concept, because

there were no osmotic rearrangements in the entire pro-

ton cycle. The author of this concept himself (P. Mitchell)

interpreted “osmotics” in terms of the existence of to-

pologically closed membranes, called coupling mem-

branes, which represent an osmotic barrier for substanc-

es in general and for protons in particular, and within

which proton transport systems exist that carry out os-

motic stabilization and enable the transport of metabo-

lites [4]. The recent discovery of the K

transport cycle

in the mitochondrial membrane, which also drives ATP

synthesis [5-9], is more consistent with the name of the

chemiosmotic concept due to the fact that the transport

of potassium ions due to its high solvating properties

(unlike proton) can significantly change the osmotic

MITOCHONDRIAL NETWORK 1597

BIOCHEMISTRY (Moscow) Vol. 88 No. 10 2023

properties of the media on both sides of the coupling

membrane, which will inevitably be accompanied by

a not always compensated transport of water to one or

another volume.

The second, not commonly recognized part of

Mitchell’s concept was the postulate that the coupling

of oxidation and phosphorylation is carried out due to

the primary transfer of a proton from one aqueous phase

washing the coupling membrane to the aqueous phase

on the other side of the membrane, followed by the

transfer of a proton from the second phase to the initial

one, while carrying out the chemical synthesis of ATP in

ATP synthase localized in membrane [10-13]. This part

included the concept of a delocalized proton, in contrast

to the concept of coupling due to a localized proton

which is also transported through the membrane without

its release into the bulk aqueous phase [14, 15]. Among

these two elements of the chemiosmotic concept,

which can be subjected to some criticism, there is one

point that remains unshakable and fundamental in this

concept – it is the postulation and proof of the genera-

tion of electric potential in coupling membranes [16].

Of the known set of coupling membranes, which in-

cludes the cell membranes of some aerobic bacteria, the

membranes of chromatophores of photosynthetic bac-

teria, the thylakoid membranes of chloroplasts and the

inner membranes of mitochondria, only the coupling

membranes of mitochondria will be discussed in this re-

view. In the latter, as a result of the operation of proton

pumps of complexes I, III and IV, an asymmetric distri-

bution of protons is achieved on both sides of the inner

membrane with a resultant increase in their concentra-

tion in the intermembrane space, which corresponds to

the cytosolic side. As a result, it would be more correct

to consider Mitchell’s primary concept chemio-electric,

and only taking into account the recent discovery of po-

tassium energetics– electro-chemio-osmotic. However,

the great value of Mitchell’s discovery as a fundamental

theory that allows us to attribute the function of cellu-

lar electric power plants to mitochondria stays beyond

doubt.

THE POSSIBILITY

OF ELECTRICITY TRANSPORT

ALONG BIOLOGICAL MEMBRANES.

STRUCTURAL BACKGROUND

In 1971, V. P. Skulachev in one of his fundamen-

tal works [17] postulated the possibility of intracel-

lular energy transport in the form of a membrane po-

tential. He wrote: “The system of intracellular (and

mitochondrial) membranes and cristae may hinder en-

ergy transfer by such a hydrophilic energy carrier as ATP.

The problem would be simplified if energy could be

transmitted along the membrane in the form of an

electric field. In this way, it would be possible, for ex-

ample, to unite in the common system thousands of

energy-producing individual enzyme complexes, which

fitted into spatially distant areas of the mitochondrial

membrane.”

One of the strongest confirmations of Skulachev’s

postulate was the discovery of the mitochondrial net-

work in the striated muscle of the diaphragm [18] and

the results of studies of its development in ontogene-

sis[19]. It was a fundamental work that broke the ex-

isting paradigm of traditional two-dimensional thinking

at that time, based on the analysis of single electron

microscopic sections. The method of reconstruction of

intracellular volume from a series of consecutive tissue

sections was used in the study, which allowed to establish

the three-dimensional organization of mitochondria.

The revealed complex structure formed by these was

called the mitochondrial reticulum. Thus, these works

were to some extent the structural basis for confirming

the hypothesis of the functioning of mitochondria as

anelectric cable.

VISUALIZATION OF MITOCHONDRIA

BY PENETRATING FLUORESCENT AGENTS

A little later, a method for visualizing mitochon-

dria in a cell using selective accumulation of a positive-

ly charged fluorescent probe (rhodamine 123, which

is a methyl ester of unsubstituted rhodamine [20]) was

introduced into practice. This discovery should also be

recognized as revolutionary, because before that, mito-

chondria in the cell were visualized almost exclusively

using transmission light microscopy [21]. The earliest,

although not very sensitive, way of visualizing mito-

chondria in a cell was the very rarely used method of

staining by Janus GreenB [22], based on the reduction

of the dye by processes of mitochondrial activity. To vi-

sualize mitochondria, it was necessary to use a dye in

high concentrations, since detection was based on a

change in the optical absorption of the dye. The use of

fluorescent dyes carrying a delocalized positive charge

in the molecule allowed the dye to accumulate in the

matrix of mitochondria in many thousands of times of

its concentration in the cytoplasm of the cell. As a re-

sult, mitochondria could be visualized in the cell using

low concentrations, while the selectivity of staining was

very high. Almost simultaneously with rhodamine 123,

ethyl ester of unsubstituted rhodamine was used to stain

structures carrying the membrane potential, which is

the driving force for accumulation of fluorescent dye

in mitochondria [23]. The simplicity of the procedure

for selective staining of mitochondria in a cell and the

development of fluorescence microscopy allowed this

approach to be quickly extended to determine the struc-

ture of the chondriome in different cells.

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BIOCHEMISTRY (Moscow) Vol. 88 No. 10 2023

VOLATILITY

OF THE MITOCHONDRIAL RETICULUM

Five years after the introduction of rhodamine dyes

for the visualization of mitochondria, the volatility of

the organization of the mitochondrial reticulum was

demonstrated for the first time. The first agent causing

the rapid transformation of the mitochondrial filament

into a series of rounded fragments (the phenomenon

was then called mitochondrial fragmentation, which

corresponds to the later name of mitochondrial fission)

was benzodiazepine diazepam, which was mitochondri-

ally toxic, potentially causing oxidative stress [24]. Later,

many classical mitochondrial drugs were placed in the

category of initiators of mitochondrial fragmentation

(rotenone, antimycin A, cyanide, oligomycin, dicyclo-

hexylcarboxyamide, etc. [25,26]). The nature of the high

volatility of mitochondrial filaments, being directly

dependent on oxidative stress, became clear [27-30].

An example of mitochondrial fragmentation caused by

rotenone, an inhibitor of mitochondrial complex I, is

shown in Fig.1.

The phenomenon of mitochondria fragmentation

(their fission) has become the subject of research for

many scientific groups, and this research continues,

as a result of which a whole set of proteins involved in

this process has been identified (e.g., see review [31]).

However, no one has yet analyzed the minimum size of

the mitochondrial fragment and its composition. This

seemingly simple question is not too trivial related to the

problem of heterogeneity of the mitochondrial popula-

tion and their asymmetric division [32-34], as a result

of which the fragmentation products formed may dif-

fer greatly in composition and subsequent fate. On the

other hand, the question remains: do all mitochondrial

fragments have mitochondrial DNA in their interior in

order to ensure at least a small degree of relative auton-

omy? However, the last question may not be too fun-

damental, given that when oxidative stress is eliminated,

the reverse process of fragmentation is observed, when

mitochondrial fragments can begin to fuse. However,

the question of how different or identical the fragments

should be in composition in order to fuse remains open.

ORGANIZATION

OF THE MITOCHONDRIAL RETICULUM

The mitochondrial reticulum can be organized in

two ways. One system is formed in such a way that the

mitochondrial matrix is uniform and forms a continuum

throughout the mitochondria, even under conditions of

their branching. An example of such an organization is

the giant mitochondrial reticulum in normal fibroblasts

(Fig.2), mammalian astroglial cells, Saccharomyces cer-

evisiae cells [35], Xenopus egg [36], and insect sperma-

tids forming the so-called nebenkern [37]. According

to the second scenario, the mitochondrial reticulum is

organized by separate small mitochondrial units, each

with its own matrix isolated from each other, united by

the dense contacts with each other. The oldest, but not

very well-known example is the mitochondria in several

spermatozoa [38-41], in particular of mammals, where

individual mitochondria, connecting to each other with

the help of a certain “cement”, thus forming the mid-

piece of the sperm, organized by these mitochondria by

helix with a different number of spiral units depending

on the type of animal. Among the diverse terminology

describing intermitochondrial formations in spermatids,

the term nuage is often found, which has a wider

Fig. 1. Fragmentation of mitochondria in embryonal porcine kidney cell culture. a)Control cells; b)after treatment with rotenone (1μM, 24h).

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Fig. 2. Mitochondrial network in human skin fibroblasts (stained with ethylrodamine). The arrow points to a fragmented mitochondrial filament.

application for describing intracellular structures [40]

(also see the review[41]). Almost 50 years ago, “inter-

membrane junctions” were described in detail in skeletal

muscle in the form of an electron-dense material con-

necting neighboring mitochondria within one cell (the

so-called four-membrane junctions, that is, covering the

space between the inner membranes of two mitochon-

dria, including both outer membranes). At the same

time, 6-membrane junctions of the same type were de-

scribed for the so-called nexus zone, where a contact

is formed between mitochondria, which also includes

two plasma membranes of neighboring cells [18, 19, 42].

Theorganization of the mitochondrial reticulum in on-

togenesis was considered in detail [19].

Almost half a century later, the same type of re-

search was reproduced [43, 44], but the novelty of these

later works was limited only by a more sophisticated

methodological base, the use of new terms “connectome”

and “interactome” and the correlation of the structur-

al organization of the mitochondrial tree with muscle

activity. The latter is an important point, because it as-

sumes the appropriate organization of the mitochondrial

reticulum in the skeletal musculature [45], which in a

best way corresponds to the energy needs of the mus-

cle cell. It should be noted that the problem of matching

energy needs and the delivery of components and energy

production in the cell (energy supply-demand problem)

is one of the key elements of the occurrence of cardiac,

brain and other cellular and organ pathologies that occur

when this match is violated, and mitochondrial organi-

zation and communication play a fundamental role in

these processes [45].

No doubt that the structural interaction of mito-

chondria with each other and with other cellular ele-

ments is only one part of intracellular communication.

Basically, this communication is realized through the

exchange of chemical signaling molecules that can be

hidden in membrane vesicles generated by various cell

elements, including mitochondria [46-49].

Ultimately, the hypothesis of the functioning of

extended mitochondrial structures as electrical energy-

transmitting cables consisted in an adequate and uni-

form supply of all cell components with electrical

energy that can be transformed into chemical energy

of the ATP.

PROOF OF THE FUNCTIONING

OF EXTENDED MITOCHONDRIAL SYSTEMS

AS ELECTRICAL CABLES

Only three years have passed since the discovery

of the fragmentation of the mitochondrial reticulum,

when experimental evidence of the functioning of the

mitochondria as an electrical cable was carried out [50].

As an object, normal skin human fibroblasts were used,

in which mitochondria normally form a single network

of very long single or branched filaments hundreds of

microns long. Since fluorescent penetrating dyes such

as rhodamine 123 or ethylrodamine can detect only

energized mitochondria (which have a membrane po-

tential that allows the dye to accumulate theoretically

up to 10,000-fold concentrations in the mitochondri-

al matrix compared to extracellular content), a change

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in the membrane potential along the entire length of the

extended mitochondria after a local lesion of the mito-

chondrial filament was noted. The lesion was carried out

using a focused laser beam, while the size of its spot was

comparable to the thickness of the mitochondrial fila-

ment and was a fraction of a micron. The experimen-

tal result confirmed the hypothesis of the equipotential

nature of the mitochondrial filament, since a local col-

lapse of the mitochondrial membrane caused complete

de-energization of the entire extended mitochondrion,

manifested in the loss of fluorescence of the mitochon-

drial dye along its entire length [50]. Later, similar ex-

periments were carried out with neonatal cardiomyo-

cytes, whose mitochondria are also organized in the

form of a branched tree. But unlike fibroblasts, where

the mitochondrial matrix is continuous and extends

over the entire length without breaks, the entire mito-

chondrial reticulum in this case is organized by separate

mitochondrial units united by means of intermitochon-

drial junctions. As a result, the mitochondrial network

of neonatal cardiomyocytes has many unconnected mi-

tochondrial matrixes. In this case, with a local lesion

of one element of the mitochondrial network, a part of

the general network was deenergized. This meant that

structurally and functionally, in a neonatal cardiomyo-

cyte, mitochondria in a single cell are organized as sep-

arate equipotential clusters, also consisting of separate

mitochondria united by intermembrane junctions [51].

The complete electrical short circuit observed under the

deenergization of a separate cluster meant that the in-

termitochondrial junctions are electrically permeable,

providing communication of neighboring mitochondrial

matrixes presumably due to the presence of ion channels

in the inner and outer membranes of the contacting mi-

tochondria. Moreover, the architecture of the cristae in

the intermitochondrial junctions was interesting– they

were located clearly perpendicular to the plane of the

contact zone, which probably facilitated the propagation

of the membrane potential through the mitochondrial

network [52].

Later, it was found that in the intermitochondrial

junctions of cardiomyocytes, which are represented by

an osmiophilic substance on electron microscopic im-

ages, a pore protein of the outer membranes, a voltage-

dependent anion channel, is abundantly present [53],

which could be considered as a structural confirmation

of ion-channel communication between mitochondria

in the junctional zone.

Subsequently, using the same approaches, an elec-

trical connection was demonstrated between the mito-

chondria of the sperm [54] and trichome cells [55]. This

also suggested the presence of ion channels in the con-

tact zone of the mitochondria of spermatozoa (which,

as we have already indicated above, were visualized as

electron dense formations, which served as the basis for

their name “mitochondrial cement” [40, 41]).

More than 25 years after the establishing and proof

of the existence of mitochondria as an electric cable,

awork from the laboratory of Robert Balaban was pub-

lished in Nature, exactly reproducing the already de-

scribed idea, principle and methodological nature of

the organization and functioning of the mitochondrial

reticulum in cardiomyocytes [56], with the only differ-

ence that a more modern methodological base was used.

Later, in a number of other publications (e.g., see [57])

from the same laboratory, for unknown reasons, unam-

biguously interpreted experiments performed in Moscow

were questioned (read ...However, there are contradic-

tory reports of the functional connectivity of the cardiac

mitochondrial reticulum [57]...), however with subse-

quent proof of the correctness of early ideas and proofs.

In addition to the examples of ignoring the primary

source of the cable theory of extended coupling mem-

branes, including the inner membranes of mitochondria,

the foundations of the cable theory of the functioning

of the mitochondrial reticulum have been criticized to

some extent, which requires special consideration [58].

On a very good methodological basis, it has been shown

that cristae within the same mitochondria can have

different transmembrane potential. The authors of this

study themselves clearly understood some discrepancy

between their data and the cable theory and offered a

reasonable explanation, the basics of which we discussed

earlier (see Fig.3 in [59]), when they cited both old and

modern data on the structure and organization of cristae

[60, 61]. These data can be conditionally presented as

evidence of the presence of submitochondrial particles

inside the mitochondria that have or do not have elec-

trical contact with the inner mitochondrial membrane,

which undermines the old ideas that mitochondrial cris-

tae form a continuum with the inner membrane. Based

on this understanding of the structure of mitochondria,

the cristae may represent separate organizations of cou-

pling membranes that do not always have an electric

connection with the inner membrane, and they may

have different transmembrane potential. At the same

time, the inner membrane of the mitochondria is a con-

tinuous and equipotential structure, and it is the materi-

al basis of the mitochondrial electrical cable theory.

However, one more scenario cannot be excluded,

which, without a critical assessment of the methodolog-

ical features of the data obtained [62], can be interpret-

ed as the absence of cable properties of extended mito-

chondria. This concerns experiments to assess the ener-

gization of mitochondria using the JC-1 dye, the fluo-

rescence of which depends on the concentration of the

probe. At high concentrations of JC-1 corresponding to

its concentration in the matrix of highly energized mi-

tochondria, so-called J-aggregates, when excited, emit

light in the red region, while in low-potential mito-

chondria, where the probe concentration is not so high,

J-aggregates are not formed, and when excited, light is

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BIOCHEMISTRY (Moscow) Vol. 88 No. 10 2023

Fig. 3. Fragmentation of mitochondria in cells. Staining with ethylrodamine. a) Normal human fibroblast. b) The same cell after 10 s of ex-

posure to excitation light. c)Electron microscopy of mitochondria in an embryonic porcine kidney cell exposed to rotenone (1μM, 24 h).

The presence of separate morphological compartments divided by septa (indicated by an arrow) can be seen.

emitted in the green region of the spectrum. So, when

using conventional fluorescence microscopy, it was no-

ticed that along one mitochondrial filament, it was pos-

sible to observe the alternation of regions with red and

green fluorescence, which could be interpreted as the

absence of equipotency along the length of the filament

and a certain alternation of low- and high-potential

compartments along the length of a single mitochondrial

filament [62].

There are two issues to consider when using and

interpreting fluorescent signals from JC-1. Firstly, this

agent is sufficiently lipophilic and will be distributed not

only in accordance with the values of the membrane po-

tential on the inner mitochondrial membrane, but also

in accordance with the lipophilic environment in the

mitochondria, which may not be the same throughout

the entire volume of mitochondria. But the main thing is

that this “multicoloration” of a single mitochondrion in

a cell does not appear immediately, but in the process of

observation, which may be the result of a photodynamic

effect, leading first to the formation of septa inside mi-

tochondrion dividing one extended mitochondrion into

a number of electrically isolated compartments (Fig.3)

with subsequent fragmentation of the mitochondrial fil-

ament.

This process of septa formation can occur within

seconds when irradiated with sufficiently strong light

that excites the dye. Electron microscopic data confirm

that during the initiation of fragmentation of the mito-

chondrial reticulum, the septa can divide the mitochon-

dria into compartments of different configurations cor-

responding to different degrees of energization (Fig.3b,

as well as Fig.6b in[29]).

There were significantly fewer critics of the elec-

tric cable theory of mitochondria than those who sup-

ported this concept. A very important work supporting

the basic principles of the cable theory was the solu-

tion of the question of how continuous the matrix is

throughout the entire space of the mitochondrial tree.

In one of the studies, a photoactivated green fluorescent

protein located exclusively in the mitochondrial matrix

was used to tag individual mitochondrial networks in

acell in combination with real-time monitoring of the

mitochondrial membrane potential [63]. At the same

time, matrix continuity was found within a single equi-

potential mitochondrial cluster. The invariable equipo-

tentiality of individual mitochondrial networks suggested

that the heterogeneous nature of the membrane poten-

tial in the mitochondria of the cell reflects the differ-

ences between individual networks.

Other researchers also came to the same conclusion

about the continuity of the matrix within one unsepted

mitochondria (a single electrical cable) and the impos-

sibility of functional communication of the matrixes of

neighboring mitochondria. The obtained data served

as a structural and functional basis for understand-

ing the morphological and functional heterogeneity of

mitochondria in the cell [64,65].

Concluding this section, we can say with sufficient

confidence that the functioning of the mitochondria as

an electrical cable is proven. However, it is likely that

mitochondrial networks may carry other hypothetical

functions, which we will discuss.

OTHER HYPOTHETICAL FUNCTIONS

OF EXTENDED MITOCHONDRIAL STRUCTURES

Ensuring uniform distribution of redox potential

throughout the cell volume. Considering a single, but unit-

ed, matrix-continuous mitochondrial network, through-

out which Δψ is the same (the entire network is equi-

potential), and the membrane potential itself reflects

the work of proton pumps driven by the oxidation of

reduced equivalents, primarily NAD(P)H, it must be

taken into account that the membrane potential in

steady state conditions should be in thermodynam-

ic equilibrium with the redox potential created by

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BIOCHEMISTRY (Moscow) Vol. 88 No. 10 2023

the pair NAD(P)H/NAD(P). In turn, this pair is in

equilibrium with the reduced glutathione/oxidized glu-

tathione (GSH/GSSG) pair, while both are the main

redox buffer systems in the cell [66].

Thus, due to the equipotential nature of the mito-

chondrial network, ideally covering the entire thickness

of the cell, this network provides a uniform distribution

of the redox potential over this volume, being in some

way a “stirrer”, not allowing the creation of large local

areas with different redox potential. The situation may

change dramatically under conditions of forced frag-

mentation/fission of the mitochondrial network, when

each mitochondrial fragment will create a redox envi-

ronment around itself in accordance with the magnitude

of the membrane potential on the inner membrane of

this fragment. Considering that fragmentation is asso-

ciated with the presence of oxidative stress, which leads

to an increase in the heterogeneity of mitochondria by

membrane potential [29, 34], the heterogeneity of the

redox potential distribution in the cell after mitochon-

drial fragmentation is quite expected.

Oxygen pipeline. It is known that the solubility of

oxygen in lipid membranes and their hydrophobic com-

ponents is higher than in the aqueous phase, as a result

of which the oxygen concentration in mitochondrial

membranes is higher than the cytosol. Even though it

is in the inner membrane of the mitochondria the main

oxygen consumer (cytochrome oxidase) is localized,

membranes can still be considered as oxygen buffers that

help facilitate the diffusion of O

along the mitochon-

drion. This will to some extent ensure the balancing of

the oxygen distribution over the cell volume and prevent

the creation of local hypoxic regions (of course, this will

greatly depend on the activity of mitochondrial respi-

ration, which determines the diameter of the so-called

Krogh cylinder (the volume distribution of oxygen in the

tissue around the capillaries carrying oxygen, depending

on the rate of oxygen supply and usage [67]).

Proton pipeline. In the case of equivalence not only

of the membrane potential along the entire length of

the mitochondria, but also of the entire electrochemical

potential of hydrogen ions (ΔμH

) [which includes not

only the values of the membrane potential, but also the

gradient of hydrogen ions (ΔpH)], the value of ΔpH will

also be the same along its entire length. With the same

pH values in the matrix, this will lead to the fact that

the environment of the giant mitochondrion will have

the same pH values, even without taking into account

the possibility of accelerated proton conduction through

the membranes by the Grothgus mechanism [68] for or-

dered water molecules in the near membrane layers [69].

Thus, as in the case of the supposed “stirring” of the re-

dox potential, the giant mitochondria will “stir” the pH

along the entire length of its environment.

Balancing intracellular concentrations of potassium

ions. Given the recently discovered mitochondrial po-

tassium energetics [6-8], driven by the transmembrane

potential, we can expect a uniform distribution of po-

tassium ions throughout the intracellular volume in the

environment of giant mitochondrion.

Thus, in many ways, the mitochondrial network

can serve as a structure that enables uniform distribu-

tion of different components throughout the cell and

serve as a kind of “stirrer” in the cell.

MEDICAL ASPECTS

In the above material, we focused on the problems

of adequate supply of the living system with the neces-

sary material for the normal course of metabolism, in

particular energy metabolism, whether it is a cell, or-

gan, or organism. Full compliance of a supply-demand

mechanism existing in a living cell defines the concept

of homeostasis, and deviations in any direction can be

fraught with the emergence of a pathological phenotype.

These deviations can be caused by physical and chemical

effects on the system, and one of these factors is the ef-

fect accompanied by the occurrence of oxidative stress.

The pathogenesis of oxidative stress is too obvious, and

giving examples of this kind takes up most of the scien-

tific literature. We can only briefly touch those medi-

cal problems that make up a small fraction of the vast

number of widely discussed neurological or cardiologi-

cal aspects, leaving aside the problems of obstetrics and

neonatology, although the problem of maintaining redox

homeostasis in cells there is no less important.

From our logical assumption that the mitochondri-

al network can serve to provide the equilibrium of the

redox potential in the cell, it follows that oxidative stress

as the cause or effect of internal disorders and subse-

quent changes in the network structure lead the intra-

cellular contents away from the equilibrium state, which

inevitably leads to a change in intracellular metabolic

homeostasis. This embraces a huge number of pathol-

ogies, and we will only take as an example the general

problems of obstetrics, gynecology, and neonatology,

which make up the leading part of morbidity and child

and adult mortality. Special attention should be paid to

oxidative stress accompanying various pathologies that

are the subject of these branches of medicine [70, 71],

in particular, such as preeclampsia, defined as hyperten-

sion and proteinuria that occurred after 20 weeks of ges-

tation and fetal growth retardation [72, 73]. One of the

causes of preeclampsia is placental implantation, which

leads to remodeling of the mother’s arteries and a de-

crease in blood flow to the fetus. This can cause a sharp

susceptibility to fluctuations in the blood flow and, as a

consequence, lead to changes in the redox status of both

placental and fetal cells, typical for ischemia–reperfu-

sion phenomenon. Reperfusion injury of the placenta

is accompanied by the generation of reactive oxygen

MITOCHONDRIAL NETWORK 1603

BIOCHEMISTRY (Moscow) Vol. 88 No. 10 2023

and nitrogen species, with the formation of oxidized

products carrying signaling and pathogenic proper-

ties with a significant increase in their concentrations,

which primarily leads to dysfunction of endothelial cells

[74,75]. Thus, these products are risk factors for cardio-

vascular diseases, which suggests a possible functional

relationship between the placenta and the cardiovascu-

lar system, and such signaling is based on components

that support or violate the redox status of the mother

and fetus [76].

It has become clear that it is mitochondria that

properly determine the redox status of the biological

system and the placenta, in particular [77-80]. As we

pointed out earlier, it is the lability of mitochondrial

structures and functions that is largely an indicator of

the redox status of the cell, and not only. The process

of mitochondrial fragmentation, as an almost manda-

tory response to the resulting oxidative stress, is also

mandatory in the mechanism of mitochondrial quality

control [29, 33]. The difference between the first and

second options is that oxidative stress leads to global

fragmentation of the mitochondrial population in a sin-

gle cell, while in the process of programmed destruc-

tion of non-functional mitochondria, fragmentation

is local, and it is preceded by internal restructuring of

mitochondria, followed by the separation of a fragment

of mitochondria with malfunctioning contents from the

mitochondrial network (which can maintain its three-

dimensional structure), and this is the principle of mi-

tophagy (mitoptosis) [29]. However, in both cases, frag-

mentation (fission) occurs with the participation of

fission proteins (e.g., Drp1 and Fis1), the level of which

in the placenta correlates with the severity of the disease

of the mother and fetus, including the weight of the latter

[81,82], which indicates a direct relationship of pathol-

ogy with the mitochondrial structure, which can serve

asan indicator of the pathological phenotype of the cell.

The evidence of the involvement of oxidative stress

in the pathogenesis and the need to maintain the rare

state of the cell and its components, primarily mito-

chondria, led to the understanding that one of the pos-

sibilities of therapeutic intervention is the normalization

of the redox status in the cells of the organ. In a recent

study using human umbilical vein endothelial cells, it

was shown that after exposure them to the blood plas-

ma of pregnant women with preeclampsia, there is a

decrease in the mitochondrial functions of these cells

associated with increased generation of reactive oxygen

species [83]. At the same time, increased expression of

TNF-α, TLR-9, and ICAM-1 inflammatory markers

was observed in the cells. Mitochondria-targeted an-

tioxidant MitoTempo reduced the production of super-

oxide by mitochondria in cells exposed to blood plasma

of pregnant women with preeclampsia, normalized mi-

tochondrial metabolism and significantly restored the

inflammatory profile of cells. These data confirm the

functional role of mitochondrial redox signaling in the

pathogenesis of preeclampsia and suggest therapeutic

pathways aimed at preserving mitochondrial structure

and functions.

Contributions. P.A.A., N.V.A., V.A.B., L.D.Z.,

S.D.Z., I.B.P., V.A.P., D.S.S., E.I.Y., D.N.S., E.Y.P.,

G.T.S., and D.B.Z. general discussion of the ideolo-

gy and future plans; D.B.Z. writing the manuscript;

D.N.S., E.Y.P., G.T.S., and D.B.Z. management and

supervision of the study; P.A.A., N.V.A., V.A.B., L.D.Z.,

S.D.Z., I.B.P., V.A.P., D.S.S., E.I.Y., D.N.S., E.Y.P.,

and G.T.S. editing the manuscript.

Funding. This work was supported by the Russian

Science Foundation (grant no.19-14-00173-P).

Ethics declarations. The authors declare no con-

flict of interest in financial or any other sphere. This ar-

ticle does not contain any studies involving animals or

human participants performed by any of the authors.

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