Article

ISSN 0006-2979, Biochemistry (Moscow), 2025, Vol. 90, No. 12, pp. 1897-1910 © Pleiades Publishing, Ltd., 2025.

Russian Text © The Author(s), 2025, published in Biokhimiya, 2025, Vol. 90, No. 12, pp. 1997-2011.

1897

REVIEW

Current Challenges and Future Directions

in Mitochondrial Potassium Transport Research

Semen V. Nesterov

1,a

*, Elena G. Smirnova

, and Lev S. Yaguzhinsky

National Research Center “Kurchatov Institute”,

123182 Moscow, Russia

Belozersky Research Institute for Physico-Chemical Biology, Lomonosov Moscow State University,

119992 Moscow, Russia

e-mail: semen.v.nesterov@phystech.edu

Received August 29, 2025

Revised October 8, 2025

Accepted November 12, 2025

Abstract— Maintenance of ionic homeostasis, particularly the balance of potassium ions as the major cat-

ions in the cytoplasm, is critically important for mitochondrial function. Uncontrolled cation influx and

the subsequent osmotically-driven water accumulation in the matrix could lead to swelling and eventual

membrane rupture. Paradoxically, despite the critical importance of potassium channels and exchangers

and their extensive research history, molecular identity of the key potassium transport systems such as

theK

exchanger and the ATP-dependent potassium channel remains a subject of ongoing debate. Within

this review and analysis of scientific publications, we outline a number of unresolved issues related to

potassium transport in mitochondria: incomplete knowledge of structural and functional rearrangements in

mitochondria upon potassium ion influx and swelling; ambiguity surrounding molecular identity of the key

potassium transport systems – the K

exchanger and the ATP-dependent potassium channel, as well as

uncertain role of ATP synthase in ion transport; and the apparent underestimation of the role of the lipid

component of the membrane in direct potassium transport and its regulation. We highlight that accumulation

of lysocardiolipin, a derivative of the key mitochondrial lipid cardiolipin, in the membrane may represent a

missing link crucial for constructing a comprehensive explanation of mitochondrial osmotic regulation mech-

anisms. Lysocardiolipin can form lipid pores that significantly enhance membrane conductance for cations.

Accumulation of lysocardiolipin could be stimulated by lipid peroxidation, could alter membrane properties,

and modulate assembly and function of the proteinaceous ion transporters. Accounting for the changes

in physical (pressure, lipid packing) and chemical properties of the membrane (peroxidation, deacylation)

during conditions that activate osmotic regulation systems is necessary for forming a holistic understanding

of potassium transport mechanisms.

DOI: 10.1134/S0006297925602783

Keywords: mitochondria, potassium transport, lysocardiolipin, oxidative stress, phospholipase A2, K+/H+-ex-

change, ATP-synthase

* To whom correspondence should be addressed.

INTRODUCTION

According to the Mitchell’s chemiosmotic theory,

electrochemical potential on the inner mitochondria

membrane is an intermediate step in accumulation

and transformation of energy [1]. Evidence of the

electric field presence and further development of the

Mitchell’s theory was presented by V. P. Skulachev,

E.A.Liberman, and their co-authors. The presence of

a negative charge in mitochondria, generation of elec-

tric field on the membrane by the respiratory chain

complexes, as well as the possibility of blocking ATP

synthesis by uncouplers, which are protonophores,

was shown in their studies [2-4]. Largely due to these

studies and numerous studies of the researchers at

that time inspired by the works of P. Mitchel and

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BIOCHEMISTRY (Moscow) Vol. 90 No. 12 2025

Fig. 1. Two states of mitochondria with transitions between them induced by potassium transport inside the mitochondria

matrix or outside of it. Changes in configuration of the inner membrane and its curvature in the process affect supramo-

lecular structure of the membrane proteins associated with oxidative phosphorylation, changing the degree of coupling

between respirasomes and ATP-synthases. Changes in the membrane curvature also cause changes in the lipid composition

of the membrane – conic lipids such as cardiolipin are re-distributed, and phospholipases could be activated in order to

adapt to the new physical properties of the membrane. IMS, mitochondrial intermembrane space.

V. P. Skulachev, this specialized area of science that

combines biochemical and biophysical approaches

was termed ‘bioenergetics’.

Oxidative phosphorylation requires rather high

electrical potential on the membrane, which for most

of the investigated organisms reaches 160-190 mV.

That is why, one of the key objections to this theory

was transport of cations to the mitochondrial matrix

under the action of electric field, which could cause

the compensatory influx of water into the matrix,

increase of osmotic pressure, and rupture of mito-

chondria. Indeed, cation flow to the matrix depends

exponentially on electric potential, and influx of

potassium ions along the potential could cause mi-

tochondria swelling by approximately 15% per min-

ute [5]. In order to prevent mitochondria rupture,

presence of the specialized transporters is necessary

in the membrane that in exchange for protons or in

symport with OH

–

expel cations outside thus main-

taining osmotic balance and mitochondria volume

[6]. The recently published studies even demonstrate

the possibility of potassium ion transport through

ATP synthase, which significantly complements the

established notions [7, 8]. Despite the fact that the

presence of potassium transport in mitochondria

has been known for a long time, this, surprisingly,

remains one of the most controversial issues in the

mitochondria research.

In this review, we present a brief description

of the existing problems and controversies, and sug-

gest the most promising, in our view, solution. The

key problems include lack of consensus regarding

POTASSIUM TRANSPORT IN MITOCHONDRIA 1899

BIOCHEMISTRY (Moscow) Vol. 90 No. 12 2025

molecular identity of the K

-exchanger and ATP-

dependent potassium channel. We suggest a con-

ceptual solution of the existing problems involving

shifting of the focus of studies from the protein

component to the role of lipids in the processes of

direct transport (formation of lipid pores), as well as

in the processes of regulation of transport systems

activity of which depends significantly on composi-

tion and structure of the lipid membrane. It is our

opinion that the more comprehensive and complex

approach considering biophysical properties of the

lipid–protein membranes, their rearrangement under

pressure during mitochondria swelling or under the

action of other stress factors such as calcium ions,

peroxidation, activation of phospholipases is neces-

sary to move forward with providing solutions to

the accumulated problems regarding the key aspects

of potassium transport and ion transport as a whole.

PROBLEM 1. EFFECT

OF POTASSIUM TRANSPORT ON STRUCTURE

AND FUNCTIONS OF THE OXIDATIVE

PHOSPHORYLATION SYSTEM

Transport of potassium ions, the main ion in

cytoplasm of eukaryotic cells, is inextricably linked

with the issue of osmotic regulation and mitochon-

dria swelling. The studies of rat liver mitochondria in

a hypotonic medium under conditions of low-ampli-

tude swelling (that does not cause membrane rupture

and is not associated with opening of a mitochondri-

al permeability transition pore (mPTP)) conducted in

our laboratory revealed that during swelling the sys-

tem of oxidative phosphorylation could turn into the

mode local coupling [9-13]. Comparison of these data

with the newest data of cryo-electron tomography

[14,15] supports the hypothesis [12] on the possibility

of clustering of the oxidative phosphorylation system

during mitochondrial cristae compression. Changes in

the membrane and changes in local curvature of the

membrane in the vicinity of the ATP-synthase dimers

cause changes in optimal orientation of the respira-

tory chain supercomplexes (respirasomes), which

changes both the average distance between the pro-

ton pumps and ATP-synthases, and leakage of protons

to endogenous uncouplers [16]. Two above-mentioned

states of mitochondria – classic state and low-ampli-

tude swelling state – are shown in Fig. 1.

It is worth also mentioning that the changes in

tension and curvature of the membrane create local

stresses and defects, which is one of the triggers of

phospholipase activation, the purpose of which is lipid

adaptation to maintain bilayer integrity. Due to this,

concentration of free fatty acids, which are endoge-

nous uncouplers, in the membrane could change, and

lysoforms of lipids also could accumulate. Considering

that the membrane curvature is higher in the com-

pressed state, this state corresponds to the highest

possible concentration of cardiolipin molecules, which

have a conic shape required for stabilization of the

curved sites of the membrane. Transition to the less

compressed state could cause partial deacetylation of

cardiolipin resulting in a temporal increase in concen-

tration of lysocardiolipin and free fatty acids. We con-

sider testing this hypothesis as one of the promising

approaches for investigation of the role of lipids in the

structural-functional rearrangements in mitochondria.

It is also worth mentioning that the change in

mitochondrial matrix swelling results in the increase

of the free water volume and decrease of macromo-

lecular crowding, which could modify functioning of

enzymatic systems under stress conditions [17]. Such

decrease in the density of matrix proteins could be

required for rearrangement of metabolic clusters with

the change of the main substrate. In particular, it is

known that the complex I could be associated with

pyruvate dehydrogenase complexes or with the com-

plexes of fatty acid beta-oxidation. In the process of

the preferrable substrate change during transition be-

tween anabolic and catabolic states [18] mitochondrial

swelling caused by temporal energy stress could also

cause, in addition to clustering of the membrane pro-

teins of oxidative phosphorylation system, increase of

mobility of matrix proteins, which is required for re-

organization of metabolic complexes – detachment of

the unfunctional dehydrogenases from the complex I

and attachment of the functional ones. Following

normalization of ATP synthesis, matrix compression

would fix the formed bond until the next stress-re-

lated swelling. Interestingly, the effect of membrane

fluidity increase on transition to the metabolically

active state has been reported also in bacteria [19],

which implies possible universality of the suggested

principle, although mechanisms of these phenomena

could differ. Testing this hypothesis could also be a

promising direction for future studies.

PROBLEM 2. UNKNOWN MOLECULAR

IDENTITY OF K

-EXCHANGER

First evidence of Na

and K

antiport exis-

tence in mitochondria was obtained by Mitchell and

Moyle [20]. Discovery of the fact that swelling of mi-

tochondria causes efflux of potassium ions from them

in the case of potential availability was the first step

in providing proof of existence of the K

-exchang-

er [21]. It was also shown that the K

-exchang-

er differs from the Na

-exchanger [22]. It was

shown in a number of studies that the mitochon-

drial K

-antiporter could be reversibly inhibited

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Fig. 2. Suggested hexamer structure of the cation /H

-exchanger LETM1. a and b) Electron microscopy image of LETM1

hexamer in negative contrast fixed at pH8. The figure is adapted from the paper by Shaoet al.[26]. c)Possible structure

of the LETM1-based cation channel.

by Mg

, protons (matrix acidification), and amphi-

philic amines, and irreversibly inhibited by 1,3-di-

cyclohexylcarbodiimide (DCCD) (see details in the

review by Garlid and Paucek [5]). Presumably, the

mitochondrial K

-antiporter is a protein with mass

82 kDa [23]. This corresponds to the known ion ex-

changer NHE7, but this protein does not have mito-

chondrial localization. One of the likely candidates

for his role, protein LETM1 (Leucine zipper-EF-hand

containing transmembrane protein 1; encoded by

the LETM1 gene), that has high homology with the

yeast cation/H

-exchanger mdm38[24,  25], was found

to be only the Ca

/2H

-exchanger [26], as well as

regulator of the membrane structure [27,  28], while

its ability to transport potassium ions in vitro was

not confirmed. At the same time, the in vivo LETM1

knockdown results in accumulation of potassium ions

in mitochondria and disruption of K

- and Na

exchange, as well as its functioning is suppressed

by magnesium ions, and in its absence is blocked

by quinine, as could be expected for the mitochon-

drial K

-exchanger  [29]. A model of one of the

functional forms of the LETM1 oligomer (performing

/2H

-exchange) with low structural resolution was

obtained by averaging the data of electron microsco-

py with negative contrasting as well as using com-

puter modeling (Fig.  2). Although, to the best of our

knowledge, no effects of DCCD (binding of which with

-exchanger is known) on LETM1 was reported,

presence of carboxyl groups (E222 in the human pro-

tein) forming an ion channel ring in the membrane

part of LETM1 hexamer structure was suggested [25]

(Fig. 2c), which comprise a suitable binding target

for DCCD. Despite this, a final experiment with iso-

lated LETM1 on liposomes testing its ability to per-

form K

-exchange has not been conducted yet [30],

hence, alternative explanations of the effect of this

gene knockout on potassium transport are possible

assuming indirect effects. Many aspects of function-

ing and regulation of LETM1 remain poorly under-

stood, and some data are controversial [31].

At the same time effect of the lipid composi-

tion of the membrane on the LETM1 function was

established, including, in particular, requirement of

cardiolipin for its functioning [32], which emphasizes

importance of investigating activity of this protein in

the membranes with natural lipid composition cor-

responding to the inner mitochondrial membrane.

It should be also mentioned that there is uncertain-

ty in evaluation of the molecular mass of the func-

tional form of LETM1. Total predicted protein mass

is around 83 kDa (based on UniProt data for human

and bovine protein), which, considering experimen-

tal errors, is in good agreement with the earlier es-

timation of the mass of K

-exchanger 82 kDa [23].

At the same time, the monomer mass in composition

of hexamer (in Fig. 2) is only around 67 kDa [26],

and according to other data, the functional form is

assembled in liposomes without first 115 aa residues

and has mass of 74 kDa [32]. The oligomeric form of

the exchanger is also questionable; according to the

data reported in one study [26], it is a hexamer with

mass 404kDa, and according to other publications the

300-kDa form is predominant, and forms with mass

500-600 kDa also exist [33]. Hence, molecular iden-

tity of the K

-exchanger in mammals has not yet

been identified fully – there is no full confidence that

this is exactly protein encoded by the LETM1 gene,

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BIOCHEMISTRY (Moscow) Vol. 90 No. 12 2025

final form of the protein formed as a result of splic-

ing, proteolysis, or posttranslational modifications has

not been clarified, as well as degree of oligomeriza-

tion; moreover, it is not known whether the homoo-

ligomers are formed in vivo or the heterooligomers

with some other proteins such as the known protein

partner, TMBIM5 [34].

At the same time, the data on the effects of lip-

id composition on the calcium ion transport through

LETM1 demonstrate the possible role of lipid rear-

rangements in regulation of this antiporter. This regu-

lation could occur either through the effect on LETM1

oligomerization, or due to participation of cardiolipin

molecule as a cofactor in ion transport. Rearrange-

ment of charged lipids between the membrane parts

also could affect potassium channels [35]. Hence, one

cannot rule out the possibility that rearrangement

of lipids or their modifications are required for the

LETM1 to become a K

-exchanger. Existence of

such regulation could be a reason why the K

-ex-

change activity was not observed in the in  vitro ex-

periments with model membranes.

Hence, the necessary step in resolving the issue

of the identity of K

-exchanger is investigation of

the ability of all possible protein candidates to me-

diate K

-exchange in  vitro in the liposomes con-

taining physiological concentrations of cardiolipin,

lysocardiolipin, and free fatty acids under conditions

of different osmotic pressure on the membrane in or-

der to model natural conditions of the K

-exchang-

er functioning in mitochondria. These investigations

should answer a question on the molecular identity

of this exchanger and its oligomeric structure; more-

over, high-resolution structure of this oligomeric form

with the help of cryo-electron microscopy (cryo-EM)

should be obtained.

PROBLEM 3. UNKNOWN MOLECULAR

IDENTITY OF THE ATP-DEPENDENT

POTASSIUM CHANNEL

Another uncertainty regarding the key compo-

nent of potassium transport in mitochondria is the is-

sue of molecular identity of the potassium ATP-depen-

dent channel (mitoK(ATP)). This channel is activated

in mitochondria under conditions of ATP deficit in the

matrix, i.e., under conditions of energy stress. Such

stress could be caused by the deficit of substrates, by

inhibitors of the respiratory chain or ATP-synthase,

by the membrane damage. The main physiological

state, when mitoK(ATP) is activated, is hypoxia, in-

cluding ischemia-induced hypoxia. Similar to the case

of K

-exchanger, pharmacological activators and

inhibitors of mitoK(ATP) have been reliably identi-

fied, as well as its physiological significance, which is

manifested, among other things, in ensuring ischemic

preconditioning, protection against oxidative damage,

and participation in osmotic regulation [36].

The existing uncertainty in understanding the

structure of this channel is quite surprising, because

this channel is one of the acknowledged and key

therapeutic targets in treating ischemia [37, 38]. De-

spite the direct fixation of ATP and K

-dependent ion

flows corresponding to activity of mitoK(ATP) in the

mitochondrial membrane established with the help of

patch-clamp technique [39], for some time even the

existence of such channel was questioned (see review

by Garlid and Halestrap [40]) mainly due to the lack

of knowledge on its molecular identity.

A mitochondria protein capable of inducing po-

tassium conductivity in the lipid membranes was

isolated already in 1980s [41]. It was shown later

that the ion transport through this 55-kDa protein is

sensitive to ATP, and antibodies against this protein

block transport of potassium ions in mitochondria,

which allowed considering this protein as a candi-

date for the role of mitoK(ATP) [42]. Moreover, a no-

tion dominated scientific literature for a long time

that the channel part of mitoK(ATP) could be formed

by the Kir6 proteins, and its regulatory ATP-binding

part – by the mitoSur proteins of the ABCfamily [43].

Nevertheless, this hypothesis contradicts some experi-

mental data [44]. It was also assumed that the ROMK

protein could form the channel part of mitoK(ATP)

[45, 46], but the experiments with knockout mice did

not confirm this [47]. At the same time, it was shown

that the protein with mass 45kDa (and its splice vari-

ant with mass 34 kDa) encoded by the CCDC51 gene

and termed by the scientists MITOK, fully correspond

to the assumed properties of the mitoK(ATP) subunit,

and, presumably, could form its channel part [48].

It was possible finally in this study to resolve numer-

ous issues, including to identify gene of this protein

and to demonstrate absence of the effects of known

inhibitors and activators of mitoK(ATP) on the potas-

sium transport in the mitochondria derived from the

mice with knockout of this gene. Nevertheless, even

the authors of this study noted the possibility of the

presence of alternative forms of mitoK(ATP) in other

tissues. Although, the question remains open on the

existence of other systems transporting potassium

ions similar in properties with mitoK(ATP), presence

of which is difficult to determine on the background

of its activity. For example, according to the data re-

ported in a few studies [7, 8], the ATP synthase with

the bound IF1 factor could perform the mitoK(ATP)-

like functions. If these methodologically thorough

experiments will be confirmed by the independent

research groups and will not provide any alternative

interpretation, this would require reconsideration

of the whole paradigm of mitochondria structure[49].

NESTEROV et al.1902

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Therefore, despite the existence of recent funda-

mental studies investigating mitoK(ATP), and that its

practical significance in medicine does not raise any

doubts, the situation exists currently, when the new

fundamental data not only do not provide answers

to the existing questions, but create more uncertain-

ty. In particular, discovery of the new MITOK protein

only increased the number of new entities (according

to Occam’s razor principle) but did not provide an-

swers on the functions of the previous protein-can-

didates for the role of mitoK(ATP), which are located

in mitochondria and affect potassium transport. Ex-

istence of different forms of mitoK(ATP) with varying

tissue-specificity or operating in different metabolic/

stress conditions (such as mitochondrial localization

of the potassium channel Kv1.3 [50]) also cannot be

ruled out.

Impossibility of recreating certain features in the

model systems and uncertainty of molecular identity

of the key potassium transporters makes one to as-

sume that the lipid component of the membrane and

its modifications could be a significant factor affect-

ing potassium transport. Thus, the issue on precise

structure of mitoK(ATP) has been transformed into

the issue on existence of other potassium channels,

which is one of the promising topics in the develop-

ment of fundamental bioenergetics. One of the pos-

sible ways to resolve the issue of uncertainty of the

status of protein-candidates is the use of cryo-EM for

determining their structure [51]. The issues described

above are closely associated with the following prob-

lem addressed below in a special section due to its

high significance.

PROBLEM 4. UNCERTAINTY

OF THE ROLE OF ATP-SYNTHASE SUBUNITS

IN POTASSIUM TRANSPORT

AND NON-SPECIFIC CONDUCTIVITY

The main fact that raises fundamental doubts in

functioning of ATP-synthase as a potassium uniporter

[7, 8] is that in the previous studies ability of this

protein to transport potassium was not observed, and

transport of even smaller in radius sodium cation re-

quired, as is well-known, modification of the structure

of c-subunits of the synthase. At the same time, the

issue with mitoK(ATP) reminds of the problem with

the search of another elusive mitochondrial structure

usually associated with transport of calcium ions, but

also playing the most important role in osmotic reg-

ulation, which is vital in the processes of cell death

and induction of inflammation – mitochondrial per-

meability transition pore, mPTP. It was shown in the

recent experiments that the c-ring of ATP synthase

could induce permeability expected for mPTP [52],

but, at the same time, modeling demonstrates impos-

sibility of pore formation by the central part of the

c-ring [53]. At present, the question of mPTP struc-

ture is one of the most controversial issues in bio-

energetics.

As an alternative version, which is rarely men-

tioned, it could be suggested that the c-subunit of

ATP-synthase induces non-bilayer lipid packing. It al-

lows to assume that disruption of the dense packing

of the F

-factor of ATP-synthase destabilizes the bi-

layer [54] similarly to the case of cobra toxin [55],

and, therefore, could cause formation of the lipid

defects or even pores, conductivity of which could

explain both nonspecific and potassium transport.

Interestingly enough, existence of the mPTP-like lipid

pores is a well-known fact [56]. It could be reliably

concluded that mPTP is not a purely lipid structure,

however, considering that the majority of scientist do

not accept the possibility that mPTP is a hybrid lip-

id-protein structure may be a reason for the failure

to finally identify its nature. The hybrid protein-lipid

nature of the pore in general does not contradict the

established understanding that formation of a pore

with participation of ATP-synthase requires dissocia-

tion of the synthase dimers and certain, not under-

stood at present, reorganization of the c-ring struc-

ture [57]. In other words, the pore is formed when

the c-subunits have a non-native structure. Formation

of defects in bilayer under these conditions could be

quite possible.

We believe that elucidation of molecular mech-

anisms of interactions of ATP-synthase with lipids,

and effect of this protein complex on transmem-

brane transport is at the moment the most urgent

problem in bioenergetics, solution of which would be

comparable in significance with chemiosmotic theory,

because it potentially could provide answers to two

questions – structure of mPTP and mitoK(ATP). In or-

der to achieve this, it is necessary to test the exist-

ing dominating hypotheses, including to investigate

in detail the effect of ATP-synthase, its oligomeric

forms, as well as its partially destabilized membrane

subunits under various conditions with empha-

sis on the role of lipids in these processes, such as

during oxidation/deacetylation of cardiolipin, accu-

mulation of free fatty acids, and excess of calcium

ions (that significantly changes lipid packing).

PROBLEM 5. EFFECT

OF LIPID MODIFICATIONS AND PHYSICAL

PROPERTIES OF THE MEMBRANE

ON POTASSIUM CONDUCTIVITY

Destabilization of lipid bilayer structure in

the process of lipid peroxidation. As has been

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BIOCHEMISTRY (Moscow) Vol. 90 No. 12 2025

mentioned above, state and composition of the lip-

id membrane itself are the most important factors

in ion transport. Primarily, these include presence of

lipid pores or defects, as well as degree of order and

saturation of acyl chains that create barrier for ions.

It is known that the increase of a number of double

bonds in lipids is accompanied by the increase of a

number of defects in the membrane and increase of

the membrane permeability for ions, including po-

tassium ions [58]. At the same time, lipid peroxida-

tion also increases permeability of the mitochondri-

al membrane lipids for potassium and calcium [59],

which is in good agreement with the fact that perox-

idation disrupts structure of the membrane, increases

surface area per one lipid molecule, because the per-

oxidized sites with acyl chains are prone to contacts

with water [60] and be exposed to interface [61].

Indeed, disruption of the membrane structure is

a known factor that increases membrane permeability

for cations as, for example, under conditions close to

lipid phase transition [62]. At the same time, pres-

ence of the peroxidized lipid forms in both layers of

the membrane bilayer is required for the increase of

membrane permeability in the process of accumu-

lation lipid peroxides, which indicates likelihood of

cluster mechanism of ion transport with their par-

ticipation [63]. However, lipid peroxidation in mito-

chondria causes increase of the relative activity of

phospholipase  A2 [64, 65], which, most likely, is as-

sociated exactly with localization of fatty acid chains

of these lipids closer to interface, where phospholi-

pase is located. Hence, under natural conditions (in

the presence of phospholipase  A2) oxidative stress is

the most important factor that increases membrane

permeability, which occurs through at least three

mechanisms: destabilization of the structure, which

causes increase of spontaneous permeability; accumu-

lation of lipid peroxidation products and formation of

clusters from them, which facilitate cation transport;

accumulation of lysophospholipids, which also are ca-

pable of cation transport (see details below).

Lysocardiolipin as a mediator of potassium

conductance. It was shown in the earlier studies

[66, 67] that lysocardiolipin increases permeability of

artificial membranes for potassium ions, similar to

ionophores such as valinomycin or nigericin. Further

detailed studies demonstrated that other lysolipids,

such as lysophosphatidylethanolamine, also increase

potassium permeability, although they are less ef-

fective in comparison with lysocardiolipin [68]. The

mechanism of transport of potassium and other ions

by lysocardiolipin, same as other lysolipids, suggests

coordination of the ion with the phosphate and hy-

droxyl groups in the lipid head. Interaction of the ion

simultaneously with several lysolipids would be opti-

mal for shielding the ion charge. The same collective

mechanism is known for ion transfer by peroxidased

lipids. Similar to the lipids subjected to peroxidation,

lysolipids also disrupt the established structure of

bilayer, have higher mobility, and could be located

closer to interface, because they have a smaller hy-

drophobic region (lower number of acyl chains). Due

to the lower hydrophobicity of lysocardiolipin in

comparison with cardiolipin, its binding to the mem-

brane proteins is weaker [69], and it does not form

large domains [70]. This facilitates its higher mobility

and free movements between the membrane layers.

It was shown that the transport of potassium ions by

lysocardiolipin involves formation of individual chan-

nels with the highest conductivity for potassium ions

[71]. Interestingly, this kind of conductivity could be

induced in the lipids extracted from mitochondria by

pre-incubation of mitochondria in the medium with

high KCl content, which indicates formation of lyso-

cardiolipin or other lipid modification occurring un-

der these conditions. Considering that the long-term

incubation in the medium with high potassium con-

tent results in influx of potassium into the mitochon-

drial matrix followed by their swelling, which also

corresponds to the conditions for activation of the

-exchanger, this indirectly suggests probable as-

sociation of lysocardiolipin accumulation with activa-

tion of the K

-exchange.

A suggested approximate structure of the potas-

sium ion bound to lysocardiolipin is presented in

Fig.  3a. A large variety of the ways of the lipid tails

and heads packing for cardiolipin is possible depend-

ing on the environment (same as, likely, for lysocar-

diolipin), therefore, establishing of exact structure

requires modeling in accordance with the particular

environment. The structure of nigericin, known anti-

biotic inducing K

-exchange in the membranes, is

presented in Fig.  3b. General similarity between these

structures is obvious – both lysocardiolipin and nigeri-

cin coordinate potassium ion and shield its charge by

the oxygen atoms. Such structure of the lipid head

could facilitate dehydration of potassium ions at the

interface and decrease the energy barrier of crossing

hydrophobic zone of the channel by the potassium

ions.

It is important to note that the main feature dis-

tinguishing the K

-exchanger nigericin from the

potassium ionophore valinomycin is presence of car-

boxyl group in the former, which provides the pos-

sibility of protonation. In the case of lysocardiolipin

only phosphate groups are present, which are strong

acids making the ability of lysocardiolipin to K

exchange very unlikely. Moreover, the presence of at

least two (in dilysocardiolipin) acyl chains makes its

flip-flop to the other side of the membrane difficult.

That is why the most probable mechanism of potas-

sium transport with participation of lysocardiolipin

NESTEROV et al.1904

BIOCHEMISTRY (Moscow) Vol. 90 No. 12 2025

Fig. 3. Possible role of lysocardiolipin in transport of potassium ions. a)Image of lysocardiolipin molecule with potassium

ion (only parts of acyl chains of lipids (gray) are shown). Oxygen atoms are shown in red color, sulfur atoms – in or-

ange, single-valent cation – in purple. b) Demonstration of similarity in coordination of cation in the nigericin molecule.

c) Normal state of the membrane without lysolipids – cations interact with cardiolipin head, but its conic shape prevents

pore formation. Cardiolipins are shown in red. d) State of the membrane under oxidative stress – dilysocardiolipin with

high surface area of the head and small tail area (shown in red) is prone to pore formation, which is optimal for cations

due to the negative charge of phosphate groups. Direction of the cation transport is determined by the gradient and electric

field (in the case of its availability). IMS, intermembrane space.

is formation of lipid pores in the membrane, which

carry negative charge and facilitate cation conduc-

tance. It is worth mentioning that cardiolipin with

its conical shape cannot form such pores due to the

steric limitations. Loss of one or two tails makes mo-

nolysocardiolipin, or even more so dilysocardiolipin,

optimal for formation of the negatively charged lip-

id pores. In the process, the heads of lysocardiolipin

molecules could shield potassium cation during cross-

ing the hydrophobic zone of the membrane, while

the lipid itself does not cross to the other side of the

membrane.

Lipid pores as an alternative to protein chan-

nels. The information presented above is summa-

rized in Fig.  4. It is specified that oxidative stress

could be considered as a universal factor activating

increase of potassium conductance across the inner

mitochondrial membrane. Specialized enzymes, acyl-

transferases, are present in mitochondria that replace

the damaged acyl chains (which are cleaved by phos-

pholipaseA2) with the new ones. The acyltransferase

tafazzin is specific for cardiolipin; it is functioning

both at the stage of synthesis of this lipid replacing

the saturated acyl chains with the unsaturated ones

(mainly with linoleic acid) and at the stage of accu-

mulation of lysocardiolipin as a consequence of oxi-

dative stress. Disruption of tafazzin functioning could

result in the development of serios pathologies such

as Barth syndrome [72]. Interestingly, there is anoth-

er acyltransferase that modifies lysocardiolipin, how-

ever, its activity, on the contrary, is associated with

increased oxidative damage and diseases [73, 74].

In addition to accumulation of lysocardiolipin,

changes in the membrane tension or its phase state,

accumulation of fatty acids, as well as increase of cal-

cium ion concentration causing significant changes in

the bilayer structure could play roles of signals ini-

tiating formation of lipid pores and, in general, lipid

bilayer defects [75]. Owing to this mechanism, con-

ductivity of the membrane could be controlled thus

exhibiting certain similarities with the properties of

-exchanger or mitoK(ATP). Formation of lipid

pores induced by palmitic acid or calcium ions is a

mechanism of regulation of the mitochondrial mem-

brane conductance operating simultaneously with

the classic cyclosporin-dependent pore mPTP and

plays an important role in protecting cells against

stress (see review by Mironova and Pavlov [76]).

POTASSIUM TRANSPORT IN MITOCHONDRIA 1905

BIOCHEMISTRY (Moscow) Vol. 90 No. 12 2025

Fig. 4. Schematic representation of events leading to the increase of cationic conductance of the membrane without par-

ticipation of protein channels, which is induced by the lipid peroxidation and causes mitochondria swelling.

Formation of lipid pores for cations could be stimu-

lated by the membrane swelling (due to increase of

membrane tension [77]), by oxidative stress (accu-

mulation of lipid peroxides and lysolipids). Changes

in concentration of the two-valent ions, calcium in

particular, also is an important factor changing sur-

face of the lipid membranes and leading to cluster-

ing of anionic lipids  [78], which also could facilitate

pore formation, especially in the cases of fluctuating

electric potential  [79]. Loss of potential on the in-

ner membrane allows efflux of the part of calcium

from the mitochondrial matrix, where it is accumu-

lated during the mitochondria functioning, especial-

ly in the case of insufficient rate of K

-exchange

(for example in the case of increased permeabil-

ity of the membrane to potassium or dysfunction

of the K

-exchanger). This makes the lipid-based

regulation system associated with formation of ly-

socardiolipin a potential mechanism duplicating the

functions of the ATP-dependent potassium channel,

and, to certain degree, functions of the K

-ex-

changer (prevention of membrane rupture during

swelling). The lipid-associated regulation system could

be a less effective evolutionary precursor of the more

specialized protein-based systems.

Another factor that must be taken into consid-

eration during formation of lysocardiolipin mediated

by phospholipaseA2, is the release of free fatty acids

that can transport protons across the membrane [80].

Certain transport proteins such as UCP, ANT, and glu-

tamate-aspartate transporter participate in the proton

transport induced by fatty acids [80]. A mechanism of

modulation of fatty acid transport has been described

for ANT [81]. That is why physiological formation of

lysocardiolipin with participation of phospholipase

is accompanied by the appearance of free fatty acid,

hence, the potassium transport is accompanied by

the proton transport. Under condition of very high

potassium concentration in the matrix at which the

transmembrane potential of potassium ions is higher

than the electrical potential, combined operation of

the potassium-conducting lipid pore and ANT could

cause movement of ions corresponding to the K

exchange. Indeed, efflux of the excess of potassium

ions from the matrix into the external medium could

create, for a short time, electric field sufficient for

ATP synthesis [82]. Hence, explosive efflux of potas-

sium due to the opening of potassium channels hy-

pothetically could support membrane potential under

extreme conditions. However, for ATP synthesis this

would require formation under the effect of electric

field of a very large difference in potassium concen-

tration between the matrix and cytosol (three orders

of magnitude difference for reaching 180 mV poten-

tial), therefore realization of this mechanism in  vivo

under conditions of very high concentration of po-

tassium ions in cytosol is impossible, and changes in

potential associated with the efflux of potassium ions

could play only a regulatory role (for example in the

processes associated with apoptosis and transport).

CONCLUSIONS

Hence, in this review we presented at least

five fundamental problems in bioenergetics that

are closely associated with the processes of potas-

sium transport: unclear effect of swelling on the

system of oxidative phosphorylation; unknown or

multiple molecular identity of the key transporters –

NESTEROV et al.1906

BIOCHEMISTRY (Moscow) Vol. 90 No. 12 2025

-exchanger and mitoK(ATP); uncertain role of

ATP synthase in potassium transport and in opening

of mPTP; extremely low knowledge on how lipid mod-

ification and physical properties of the membrane

affect potassium conductivity. In addition to these

problems discussed in detail, lack of comprehensive

mathematical models of ion transport should be also

noted, however, we did not focus on this problem, be-

cause it is impossible to develop such model without

answering the questions presented above. As a con-

ceptual solution for the emerging crisis in bioenerget-

ics associated with ion transport, we suggest shifting

attention of the researchers from the protein-based

transporters to complex consideration of protein–lipid

membranes with emphasis on the lipid components

of the membrane. Among other things, this implies

transition to more physiologically justified models of

the mitochondrial membrane containing cardiolipin

and lysocardiolipin, as well as conducting investi-

gation with varying viscosity, phase state, fatty acid

composition, and other parameters of the membrane.

Abbreviations

DCCD 1,3-dicyclohexylcarbodiimide

mitoK(ATP) mitochondrial ATP-dependent potassi-

um channel

mPTP mitochondrial permeability transition

pore

Contributions

S. V. Nesterov – preparation of the main test and illus-

trations; S. V. Nesterov, E. G. Smirnova, and L. S. Yagu-

zhinsky participated in collecting and analyzing the

data, in editing of the manuscript.

Funding

This work was carried out within the State Assignment

of the National Research Center “Kurchatov Institute.”

Ethics approval and consent to participate

This work does not contain any studies involving hu-

man and animal subjects.

Conflict of interest

The authors of this work declare that they have no

conflicts of interest.

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