Article

ISSN 0006-2979, Biochemistry (Moscow), 2025, Vol. 90, No. 12, pp. 2027-2040 © The Author(s) 2025. This article is an open access publication.

Russian Text © The Author(s), 2025, published in Biokhimiya, 2025, Vol. 90, No. 12, pp. 2139-2152.

2027

Mitochondria in Developing Brain:

Contribution of Deviations to Higher Susceptibility

to Neurodegeneration in Latter Periods of Life

Natalia A. Stefanova

1,a

*, Natalia A. Muraleva

, Diana V. Sityaeva

Mikhail A. Tyumentsev

, and Nataliya G. Kolosova

Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences,

630090 Novosibirsk, Russia

University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA

e-mail: stefanovan@mail.ru

Received September 18, 2025

Revised October 8, 2025

Accepted October 11, 2025

Abstract— It has been proven that the preclinical period of the sporadic (>95% of cases) form of Alzheimer’s

disease (AD) can last for decades, but the question of when the disease begins to develop and what contrib-

utes to it remains open. It is hypothesized that vulnerabilities to AD may be influenced by anatomical and

functional brain parameters formed early in life. This is supported by our research on the senescence-accel-

erated OXYS rats – a unique model of AD. The delayed brain maturation observed in these rats is associated

with insufficient glial support, a key regulator of neural network function, and the development of AD signs

in the OXYS rats is preceded and accompanied by the mitochondrial dysfunction. This raises the question of

whether the structural and functional features of mitochondria could influence brain maturation and thus

determine predisposition to the later development of AD signs. In this study, we compared mitochondrial

biogenesis, their trafficking, and structural state in the neuronal cell bodies, axonal and dendritic processes,

as well as activity of the mitochondrial dynamics processes in the prefrontal cortex and hippocampus of OXYS

and Wistar rats (control) during the period of brain maturation completion (from birth to 20 days of age).

Changes in the number and ultrastructural parameters of mitochondria were compared with the parameters

of dynamics processes, assessed by the frequency of mitochondria undergoing fusion or fission, the content

of the key biogenesis protein PGC-1α, and proteins mediating mitochondrial dynamics (mitofusins Mfn1 and

Mfn2, dynamin-1-like protein DRP1). In OXYS rats, deviations in formation of the mitochondrial apparatus in

the early postnatal period were identified, which may contribute to the delayed brain maturation of these

rats, promote mitochondrial dysfunction, reduce synaptic density, and ultimately lead to the neuronal death

and development of the early neurodegenerative changes.

DOI: 10.1134/S0006297925602874

Keywords: mitochondria, early postnatal period, neurodegeneration, Alzheimer’s disease, senescence-acceler-

ated OXYS rats

* To whom correspondence should be addressed.

INTRODUCTION

By 2050, global population of individuals aged

60 and older is expected to reach approximately

2 billion (WHO, 2018), with over 150 million people

suffering from Alzheimer’s disease (AD), which is

becoming the leading cause of senile dementia [1].

Consequently, the relevance of elucidating molecular

and biological prerequisites and mechanisms of AD

development, as well as developing early diagnostic

and preventive methods based on this knowledge, is

only increasing. Modern diagnostic methods have es-

tablished that the preclinical period of the sporadic

(>95% of cases) form of AD can last for decades, but

STEFANOVA et al.2028

BIOCHEMISTRY (Moscow) Vol. 90 No. 12 2025

the question of when the disease begins to develop and

what contributes to it remains a subject of debate [2].

According to the results of epidemiological and

experimental studies in recent years, the prerequi-

sites for reduced cognitive abilities in later life and

accelerated aging – the main risk factor for AD de-

velopment – may already form in the early postna-

tal period, when the brain development is completed

[3-10]. This is also supported by our research on the

senescence-accelerated OXYS rats – a unique model of

sporadic AD. We identified features of brain matura-

tion in OXYS rats during the early postnatal period

(from birth to 20 days of age) that could serve as

prerequisites for the development of early neurode-

generative changes [11-13]. In particular, we showed

that the completion of brain development in OXYS

rats occurs against the background of reduced as-

trocytic and microglial support in the hippocampus

and prefrontal cortex – key regulators of neural net-

work function. Insufficient glial support may be the

cause of the reduced efficiency of interneuronal con-

tact formation observed in OXYS rats, allowing it to

be considered a key event on the path to the later

development of AD signs [14]. At the same time, we

previously showed that the development of AD signs

in the OXYS rats is preceded and accompanied by the

age-related mitochondrial dysfunction [15-18]. Thus,

we confirmed validity of the “mitochondrial cascade

hypothesis” [19, 20], according to which pathogenesis

of the sporadic AD is based on the age-related mi-

tochondrial dysfunction. Our studies using OXYS rats

also allowed us to raise the question on whether the

genetically determined structural and functional fea-

tures of mitochondria could influence the process of

brain maturation in the early postnatal period and

thus determine predisposition to the later develop-

ment of AD.

This study aims to investigate the features of

mitochondrial biogenesis, their structural state in

the neuronal cell bodies, axonal and dendritic pro-

cesses, as well as activity of mitochondrial dynamics

and trafficking processes in the prefrontal cortex and

hippocampus of OXYS rats during the early postnatal

period, and to assess their possible contribution to

the development of early neurodegenerative changes

in the future.

MATERIALS AND METHODS

Animals. The study was conducted with male

Wistar and OXYS rats at the Shared Research Facility

“Gene Pools of Laboratory Animals” of the Institute

of Cytology and Genetics, Siberian Branch of the Rus-

sian Academy of Sciences. Animals were kept under

standard laboratory conditions (22  ±  2°C and a 12-h

light/dark cycle) in cages (57  ×  36  ×  20  cm) with free

access to water and standard granulated food for lab-

oratory animals (BioPro, Russia).

Electron microscopy. Rats were euthanized

with carbon dioxide and decapitated. Prefrontal cor-

tex and hippocampus were isolated, from which tis-

sue samples of cubic shape (2  ×  2  ×  2  mm) were cut.

The isolated brain fragments were fixed in a buffer

(2.5% glutaraldehyde, 1.5% paraformaldehyde, 0.1  M

cacodylate buffer) for 1 h at room temperature (RT),

washed twice in a buffer, post-fixed with a 1% aque-

ous solution of osmium tetroxide containing several

crystals of potassium ferricyanide (K

[Fe(CN)

]) for

1  h at RT, and incubated in a 1% aqueous solution of

uranyl acetate overnight. The next day, the samples

were dehydrated in a series of ethanol and acetone

solutions and embedded in an Epon 812 resin (Elec-

tron Microscopy Sciences, USA). Complete polymer-

ization of the samples was achieved by maintaining

them at 60°C for 3 days. Ultrathin sections (65  nm)

were obtained using a Leica Ultracut EM UC6 ultrami-

crotome (Leica Microsystems GmbH, Germany). Sec-

tions were examined using a JEOL JEM 1400 electron

microscope (JEOL Ltd., Japan) at the Shared Research

Facility for Microscopic Analysis of Biological Objects

(ICG  SB  RAS, Novosibirsk, Russia) at magnifications of

2800× and 3500× (neuronal body) and 12,000× (neuro-

pil). Identification of brain structures (Layer IV of the

prefrontal cortex (Bregma  4.68 – Bregma 3.72  mm)

and the CA1 field of the hippocampus (Bregma –

2.28 – Bregma – 3.60 mm)) was performed according

to Paxinos and Watson [21].

To assess structural and functional parameters of

mitochondria in OXYS and Wistar rats (n  =  3), 40-60

pyramidal neurons of the prefrontal cortex (at ages 0,

7, 14, and 20 days) and hippocampus (at ages 7, 14,

and 20 days) were analyzed. To assess parameters of

mitochondria in the neuropil of the prefrontal cor-

tex and hippocampus of OXYS and Wistar rats (n = 3),

3-4 sections were obtained from each animal, and 15

photographs were taken for each section, totaling

45-60 photographs per rat. Statistical analysis was

performed based on averaged data for each section

from each animal (n  =  12-15 per group). Using ImageJ

software, ultrastructure of mitochondria, their quan-

tity, and localization in neuronal bodies, axonal and

dendritic processes, as well as activity of mitochon-

drial dynamics processes, were evaluated. The fol-

lowing criteria were used to assess ultrastructure of

mitochondria: 1) intact mitochondria – intact cristae,

mitochondrial membranes, absence of degranulation,

and hydration of the mitochondrial matrix; 2)  mod-

erately altered mitochondria – partially disrupted

cristae structure, degranulation, hydration of the mi-

tochondrial matrix with formation of vacuolar “cav-

ities” within the mitochondrion, visually estimated

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BIOCHEMISTRY (Moscow) Vol. 90 No. 12 2025

to reach about 15-50% of its area; 3)  severely altered

mitochondria – extremely disrupted cristae structure:

abnormally thinned cristae, loss of original appear-

ance; degranulation, hydration of the mitochondrial

matrix more than 50% of the mitochondrial area;

in this case, mitochondria are significantly enlarged

(“swollen”)/loss of integrity (“rupture”) of the outer

mitochondrial membrane [15].

Western blot analysis. Samples of the prefron-

tal cortex and hippocampus of Wistar and OXYS rats

at ages 0, 7, 14, and 20 days (n  =  5-6) were homoge-

nized using a RIPA lysis buffer with addition of prote-

ase and phosphatase inhibitors (Sigma-Aldrich, USA).

Concentration of total protein was determined using

bicinchoninic acid (BCA) (Thermo Fisher Scientific,

USA). Proteins were separated by electrophoresis in

a 10% polyacrylamide gel, transferred to a nitrocel-

lulose membrane (Bio-Rad, USA), and blocked with

5% bovine serum albumin in 10  mM phosphate-buff-

ered saline (pH 7.4) for 1  h. The membrane was next

incubated at 4°C overnight with primary antibodies

against PGC-1α, Mitofusin  1, Mitofusin  2, Drp1, be-

ta-actin (ab54481, ab57602, ab50838, ab56788, ab1801,

Abcam, USA; 1  :  1000), Miro1, Miro2, Trak1, and

Trak2 (PA572835, PA596182, PA570029, MA527606,

Invitrogen, USA; 1  :  1000) and for 1  h with second-

ary anti-rabbit and anti-mouse antibodies (ab6721

and ab97046; Abcam; 1  :  5000). Signal intensity was

detected using a ChemiDoc MP imaging system (Bio-

Rad) and evaluated using ImageJ software (NIH, USA).

Statistical analysis. Statistical analysis was

performed using the Statistica 10.0 software pack-

age (Statsoft, USA). Factorial analysis of variance

(ANOVA) with post hoc comparison of group means

(Newman–Keuls test) was used. Data are presented as

M ± S.E.M. Differences were considered statistically

significant at p  <  0.05.

RESULTS

Mitochondrial biogenesis, quantity, and struc-

tural state in the early postnatal period. Mitochon-

dria are dynamic structures with close relationship

between their morphology and functionality. Their

number, size, and shape are determined by the pro-

cesses of biogenesis, fission, fusion, and mitophagy;

they actively interact with other organelles, form-

ing membrane contacts [22]. The state of mitochon-

drial biogenesis in neurons of the prefrontal cortex

and hippocampus of OXYS and Wistar rats in the

early postnatal period was assessed based on the

level of the key protein PGC-1α (peroxisome prolif-

erator-activated receptor gamma coactivator 1-al-

pha) [23]. ANOVA analysis showed that the level of

PGC-1α depended on the genotype of the animals

and was lower in OXYS rats in the prefrontal cortex

1,32

  =  8.26, p  <  0.008; Fig. 1, a and c) and hippocam-

pus (F

1,32

  =  14.13, p  <  0.001; Fig.1, b and d). According

to the comparison of the group means, the level of

PGC-1α was significantly lower in OXYS rats in both

brain structures (p  <  0.05) at birth and at 7 days of

age – in the hippocampus (p  <  0.05).

The efficiency of mitochondrial apparatus for-

mation in the pyramidal neurons of the prefrontal

cortex and hippocampus of OXYS and Wistar rats

in the early postnatal period was assessed by their

quantity and structural state using electron micros-

copy (EM) (Fig. 1e). The number of mitochondria in

the neuronal bodies of the prefrontal cortex of both

rat strains changed unidirectionally during this peri-

od (F

3,143

  =  3.6, p  <  0.02; Fig. 1f). In the hippocampus,

it depended on the genotype (F

1,316

  =  7.99, p  <  0.005)

and age (F

2,316

  =  5.8, p  <  0.004; Fig.1g) of the animals.

In Wistar rats, the number of mitochondria was max-

imal at 7 days of age and decreased by two weeks

of age (p  <  0.001). In OXYS rats, on the contrary, the

number of mitochondria in the neuronal bodies was

minimal at 7 days of age and increased by 20 days

of age (p  <  0.01). As a result, density of the neuronal

mitochondria in OXYS rats at 7 days of age (p  <  0.01)

was lower, and at 14 and 20 days of age – higher

(p  <  0.01 and p  <  0.001, respectively) compared to the

age-matched Wistar rats.

ANOVA analysis showed that the number of

mitochondria in the neuropil (axonal and dendrit-

ic processes) of the prefrontal cortex and hippo-

campus (Fig.  1, h and i) depended on the genotype

1,91 

=  13.2, p  <  0.0005 and F

1,66 

=  18.5, p  <  0.0001,

respectively) and increased with age in the rats of

both strains (F

3,91

  =  136.4, p  <  0.0001 and F

2,66 

=  90.1,

p  <  0.0001, respectively). However, in OXYS rats, this

parameter was higher at 14 days of age in the hippo-

campus and at 20 days of age in both brain structures

(p  <  0.01 for all) compared to Wistar rats.

Assessment of mitochondria by their structural

state. Evaluation of the mitochondria based on their

structural state revealed that in the prefrontal cor-

tex of the rats from both strains during the early

postnatal period the specific content of organelles

with intact ultrastructure changed unidirectionally

3,313 

=  26.7, p  <  0.0001) and was maximal at 14 days

of age and minimal at 20 days of age (Fig. 2a). The

content of mitochondria with moderately altered ul-

trastructure also depended solely on age (F

3,313

  =  18.6,

p  <  0.0001): in both Wistar and OXYS rats this param-

eter decreased by two weeks of age and tripled by

20days of age. The specific content of organelles with

pronounced alterations decreased in both rat strains

by one week of age and increased by 20 days of age

3,313 

=  13.4, p  <  0.0001) and was higher in OXYS rats

at 7 and 20 days of age (F

1,313

  =  6.1, p  <  0.02).

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BIOCHEMISTRY (Moscow) Vol. 90 No. 12 2025

Fig. 1. Content of PGC-1α protein in the prefrontal cortex (PFC) (a) and hippocampus (b) of Wistar and OXYS rats during

the postnatal completion of brain maturation. Representative blot images in the PFC (c) and hippocampus (d). Beta-actin

was used as a control. Representative EM images of a pyramidal neuron (e, upper panel) and neuropil (e, lower panel).

Mitochondria (m) are located in the neuron cytoplasm. The neuron body is surrounded by neuropil; mitochondria are

visible in axonal and dendritic processes (yellow arrows). Numbers of mitochondria per 100 µm

of neuron cytoplasm

and in the neuropil in the PFC (f, h, respectively) and hippocampus (g, i, respectively) are shown. Data are present-

ed as M  ±  S.E.M. * Significant differences compared to the age-matched Wistar rats; # compared to the previous age.

Differences were considered statistically significant at p < 0.05.

In the hippocampus of both rat strains (Fig. 2b),

the specific content of organelles with intact ultra-

structure was maximal at one week of age, decreased

by 20 days of age (F

2,193

  =  89.2, p  <  0.0001), and was

lower in OXYS rats (F

1,193

  =  4.8, p  <  0.03). The content

of mitochondria with moderately altered ultrastruc-

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Fig. 2. Specific content of mitochondria in the neurons by the degree of their structural degradation in the prefron-

tal cortex (a) and hippocampus (b). Representative electron microscopy (EM) image of a pyramidal neuron (N) and

neuropil (neuropil) in the CA1 field of the hippocampus of the 14-day-old OXYS rats (c). Mitochondria (m) with mod-

erately pronounced destructive changes (yellow dashed line). Data are presented as M ± S.E.M. * Significant differenc-

es compared to the age-matched Wistar rats; # compared to the previous age. Differences were considered statistically

significant at p < 0.05.

ture (Fig. 2c) depended only on age (F

2,193

  =  61.6,

p  <  0.0001): in both Wistar and OXYS rats, this param-

eter increased by 20 days of age. The specific content

of organelles with pronounced alterations was high-

er in OXYS rats (F

1,193

  =  6.6, p  <  0.02) and increased

by 20 days of age in both rat strains (F

2,193

  =  54.8,

p  <  0.0001).

Mitochondrial dynamics in the early postnatal

period. Processes of mitochondrial dynamics were

assessed by the presence of contacting mitochondria

undergoing fusion or fission (Fig. 3a). It was found

that the specific content of such mitochondria in the

neuronal bodies of the prefrontal cortex did not de-

pend on age (F

3,143 

=  0.05, p  =  0.98) and was signifi-

cantly lower in OXYS rats in comparison with Wistar

rats at 14 and 20 days of age (p  <  0.05; Fig. 3b), in-

dicating significant decrease in the intensity of mito-

chondrial dynamics. In the hippocampus of both rat

strains, the proportion of contacting mitochondria

was maximal at 7 days of age and decreased by two

weeks of age (F

2,315

  =  3.9, p  <  0.05; Fig. 3c). In the

neuropil, this parameter depended only on age – it

decreased by 14 days of age and increased by 20 days

of age in the prefrontal cortex (F

3,91 

=  5.3, p  <  0.003;

Fig. 3d) and, conversely, decreased by 20 days of age

in the hippocampus (F

2,66 

=  3.4, p  <  0.05; Fig. 3e) of

both rat strains.

Proteins Mfn1 and Mfn2, which are directly in-

volved in the regulation of mitochondrial dynamics,

play a key role in the process of mitochondrial fu-

sion, while Drp1 is necessary for their fission and

mitophagy [24]. Assessment of the changes in their

content during the early postnatal period in the

brains of OXYS and Wistar rats was performed using

Western blot analysis.

In the prefrontal cortex (Fig. 4a), the content of

Mfn1 changed unidirectionally with age in the rats

of both strains (F

3,40 

=  6.069; p  <  0.002), with the lev-

el significantly increasing by 14 days of age and de-

creasing by 20 days of age in Wistar rats (p  <  0.002

for both). The content of Mfn2 depended on geno-

type of the animals (F

1,40

  =  40.2; p  <  0.001): in OXYS

rats, its level was lower at birth, at 7 days, and at

20 days of age, but higher at 14 days of age com-

pared to the age-matched Wistar rats (p  <  0.001,

p < 0.012, p  <  0.001, and p  <  0.009, respectively).

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Fig. 3. Representative EM images of the neuropil; axonal processes contain mitochondria undergoing fission/fusion (yellow

arrows). The right panel shows mitochondria at higher magnification (a). Specific content of mitochondria undergoing

fission/fusion, relative to the total number of mitochondria in neuronal bodies (b, c) and neuropil (d, e) of the prefrontal

cortex and hippocampus. Data are presented as M ± S.E.M. * Significant differences compared to the age-matched Wistar

rats; # compared to the previous age. Differences were considered statistically significant at p < 0.05.

With age, the content of Mfn2 changed in both rat

strains (F

3,40

  =  4.3; p  <  0.010), but its dynamics dif-

fered. In Wistar rats, the level of Mfn2 decreased by

7 days of age (p  <  0.008) and increased by 20 days

of age (p  <  0.001). In OXYS rats, the level of Mfn2

increased from 7 to 14 days of age (p  <  0.001) and

decreased by 20 days of age (p  <  0.001).

ANOVA analysis showed that the content of

Drp1 in the prefrontal cortex depended on genotype

1,40

  =  51.5; p  <  0.0001): at 7 and 20 days of age, its

level was higher in OXYS rats (p  <  0.001 and p  <  0.005,

respectively), which may indicate enhancement of

mitochondrial fission processes. This is also support-

ed by the lower Mfn1/Drp1 (F

1,40

  =  21.9; p  <  0.0001)

and Mfn2/Drp1 (F

1,4040

  =  91.2; p  <  0.0001) indices in

OXYS rats compared to Wistar rats, reflecting the

state of the balance between fusion and fission pro-

cesses.

In the hippocampus (Fig. 4b), the content of

Mfn1 and Mfn2 also changed unidirectionally with

age in both rat strains (F

3,4040

  =  11.1; p  <  0.001 and

3,40

  =  5.0; p  <  0.005, respectively), and their levels

at birth were lower in OXYS rats (p  <  0.01 and

p  <  0.034, respectively). The content of Drp1 in the

hippocampus of rats depended on age (F

3,440

  =  15.5;

p  <  0.001): in Wistar rats, its level increased by two

weeks of age (p  <  0.001), while in the OXYS rats, it in-

creased by the end of the first week of life (p  <  0.02)

and decreased by 20 days of age (p  <  0.015). As a

result, the content of Drp1 in OXYS rats was higher

at 7 days of age and lower at 20 days of age com-

pared to Wistar rats (p  <  0.002 and p  <  0.015, respec-

tively).

Assessment of the balance between fusion/fission

processes (Mfn1/Drp1 and Mfn2/Drp1 indices) showed

its change during the early postnatal period in both

rat strains (F

3,4040

 = 5.3; p  <  0.003 and F

3,40

 = 5.1;

p  <  0.005, respectively). In OXYS rats, the Mfn1/Drp1

ratio increased by 14 and 20 days of age (p  <  0.015

and p  <  0.05, respectively), and the Mfn2/Drp1 ratio

increased by 20 days of age (p  <  0.017). In Wistar

rats, the Mfn2/Drp1 ratio decreased by two weeks of

age (p  <  0.050). Meanwhile, in OXYS rats, the decrease

in Mfn1/Drp1 and Mfn2/Drp1 during the first week

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Fig. 4. Changes in the content of Mfn1, Mfn2, and Drp1 in the prefrontal cortex (a) and hippocampus (b) of Wistar and

OXYS rats during the early postnatal period according to Western blot analysis. Representative blot images and relative

amounts of Mfn1/2, Drp1, Mfn1/Drp1, and Mfn2/Drp1, normalized to beta-actin. Data are presented as M ± S.E.M. (n = 6).

* Significant differences compared to the age-matched Wistar rats; # compared to the previous age. Differences were con-

sidered statistically significant at p < 0.05.

oflife (p  <  0.05) indicates enhancement of fission pro-

cesses, while the increase in their levels at 20 days of

age indicates mitochondrial fusion.

Mitochondrial trafficking in the early postna-

tal period. To assess the state of mitochondrial traf-

ficking in neurons, Western blot analysis was used

to determine the level of adaptor proteins of the

mitochondrial transport system – GTPases Miro1 and

Miro2, which ensure binding of mitochondria to the

transport proteins – dyneins and kinesins [25] – in

the prefrontal cortex and hippocampus of OXYS and

Wistar rats in the early postnatal period. The content

of transport proteins – kinesins TRAK1 and TRAK2

[26] – was also studied.

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Fig. 5. Changes in the content of Miro1/2, Trak1/2 in the prefrontal cortex (a) and hippocampus (b) of Wistar and OXYS

rats in the early postnatal period according to the Western blot analysis (n = 5). Representative blot images and rel-

ative amounts of Miro1/2, Trak1/2, normalized to beta-actin. Data are presented as M ± S.E.M. * Significant differenc-

es compared to the age-matched Wistar rats; # compared to the previous age. Differences were considered statistically

significant at p < 0.05.

According to the results of ANOVA analysis, in

the prefrontal cortex (Fig. 5a) of Wistar and OXYS

rats, the content of Miro1, Trak1, and Trak2 did not

depend on genotype and did not change with age

(p  >  0.05). The content of Miro2 was higher in OXYS

rats at 7 and 14 days of age (F

1,40

  =  4.57; p  <  0.038),

and by 20 days of age, interline differences were

leveled off against the background of its decrease in

OXYS rats (p  <  0.01).

In the hippocampus of Wistar and OXYS rats,

the content of Miro1/2, Trak1/2 (Fig. 5b) did not de-

pend on genotype of the animals and did not change

with age (p  >  0.05). It should be noted that from 14

to 20 days of age, the content of Trak2 in OXYS rats

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Fig. 6. Representative electron microscopy (EM) image of a neuropil. Axonal (A, pseudo-colored purple, lower panel) and

dendritic (De, pseudo-colored green, lower panel) processes contain mitochondria (m). Pre- (Pre) and postsynaptic (PSD)

compartments of the synapse (a). Specific content of mitochondria in dendritic (b, c) and axonal (d, e) processes of neu-

rons in the prefrontal cortex and hippocampus. Data are presented as M ± S.E.M. *Significant differences compared to the

age-matched Wistar rats; # compared to the previous age. Differences were considered statistically significant at p < 0.05.

increased (p  <  0.02), but was not significantly higher

than in Wistar rats.

Additionally, assessment of the specific content of

mitochondria in the dendritic processes of neurons

in the prefrontal cortex and hippocampus of Wistar

and OXYS rats did not reveal interline differences or

age-related changes (Fig.6, a-c). Regarding the axonal

mitochondria, in the hippocampus of OXYS rats at 14

days of age, their specific content was lower than in

Wistar rats (p  =  0.052; Fig. 6e). In the prefrontal cor-

tex, this parameter was lower at 7 and 14 days of

age (p  <  0.05) and higher at 20 days of age (p  <  0.01;

Fig. 6d), which is indicative of the changes in neuro-

nal mitochondrial trafficking.

DISCUSSION

It is assumed that anatomical (number and con-

nectivity of neurons) and functional (ability to en-

gage alternative neural networks) parameters of the

adult brain formed in the early period of life could

influence its vulnerability to the development of AD

and the brain’s ability to realize its compensatory

reserves [27]. Successful differentiation and matura-

tion of neurons, formation of neural networks, and

completion of brain formation as a whole is opti-

mal when mitochondrial biogenesis in the develop-

ing brain corresponds to the demand for energy re-

sources [23]. In the early postnatal period, the rate

of metabolism, energy consumption, and blood flow

in the brain are significantly higher than in the adult

organism (in mice – 3-7 times higher in the first 2-3

weeks of postnatal life, in humans it is elevated until

the age of 5) [28]. It is obvious that the process of

completing brain maturation in the early postnatal

period could potentially be influenced by disruptions

in any mitochondrial functions: calcium homeostasis,

generation of reactive oxygen species, regulation of

apoptosis, mitochondrial biogenesis, their dynamics,

mitophagy, and trafficking – movement of mitochon-

dria toward sites with increased energy consumption

in response to growth factors. In this study, we com-

pared the features of mitochondrial apparatus forma-

tion in the cortex and hippocampus of Wistar and the

senescence-accelerated OXYS rats – a model of spo-

radic AD – from birth to 20 days of age, the period

of brain formation completion.

Mitochondria play a key role in neurogenesis, reg-

ulating transition of the neural stem cells into neural

progenitor cells and, ultimately, into neurons [29-31].

Neurogenesis in the rat hippocampus occurs in waves:

it begins prenatally and continues into the postnatal

period [32, 33]. The peak of neurogenic activity in rats

occurs at 7 days of age [34], which corresponds to the

development of the fetal brain in the third trimester

STEFANOVA et al.2036

BIOCHEMISTRY (Moscow) Vol. 90 No. 12 2025

of gestation in humans – a period particularly critical

for human nervous system development. We found

that by the end of the first week of life, the number

of mitochondria in the neuronal bodies of OXYS rats

is lower in the hippocampus, while proportion of the

organelles with pronounced structural alterations is

higher compared to Wistar rats.

Simultaneously with neurogenesis and migration,

the newly formed neurons begin to establish contacts

with each other, which later develop into synaps-

es. During migration of immature neurons to their

functional sites, selective apoptotic selection occurs,

resulting in the neuroblasts of a specific phenotype.

This is followed by the second wave of selective selec-

tion associated with integration of the newly formed

neurons into the neural network [35]. The axons

and dendrites of the newly formed neurons contin-

ue to grow and mature during the first 2-3 weeks

of postnatal development, reaching mature morphol-

ogy by the end of the first month of life. Increased

expression of the primary regulator of mitochondri-

al biogenesis, PGC1α, leads to the enhanced growth

of neuronal processes and increase in the number

of mitochondria within them (without reduction in

their number in the neuronal body) [23]. We found

that brain maturation in OXYS rats during the early

postnatal period occurs against the background of re-

duced mitochondrial biogenesis, as indicated by the

lower PGC1α levels in the prefrontal cortex and hip-

pocampus compared to Wistar rats. Earlier, we iden-

tified the signs of impaired differentiation of neural

stem cells, a delayed peak of neurogenesis in the

dentate gyrus [12], a delay in the pre- and postnatal

waves of apoptosis [11], and reduction in the density

of neuronal processes and synapses [36] in the hippo-

campus and prefrontal cortex of OXYS rats during the

early postnatal period. It must be emphasized that

all these signs of delayed neuronal maturation in the

brains of OXYS rats are manifested under conditions

of insufficient astrocytic and microglial support [14].

Changes in the mitochondrial morphology are

characteristic of both differentiated and pluripotent

stages of the neuronal and glial cells in embryonic

and adult neurogenesis [31, 37]. Retrograde signaling

from mitochondria to the nucleus regulates transcrip-

tion of the genes responsible for differentiation and

determines changes in the mitochondrial dynamics

during differentiation of the neural stem cells [38].

Drp1 regulates mitochondrial remodeling cycles, in-

ducing their division to stimulate glycolytic metabo-

lism, while Mfn1/2 plays a key role in mitochondrial

fusion to promote oxidative phosphorylation [24, 31].

Analysis of our results indicates reduction in the ac-

tivity of fusion processes (assessed by Mfn1/2 levels)

and enhancement of mitochondrial fission (increased

Drp1 levels) in the brains of OXYS rats during the

first week of life. This is further supported by the

Mfn1/Drp1 and Mfn2/Drp1 indices, which reflect the

balance between fusion and fission processes.

By the end of the second week of life, the num-

ber of mitochondria in the neuronal bodies and

neuropil of the hippocampus of OXYS rats becomes

higher than in Wistar rats. By this age (14 days), the

number of mitochondria in the neuronal bodies and

neuropil of the prefrontal cortex increases in both rat

strains, and proportion of the organelles with intact

ultrastructure reaches its maximum. However, OXYS

rats exhibit reduced mitochondrial dynamics activity:

proportion of the organelles undergoing fusion/fission

in the neuronal bodies is significantly lower than in

Wistar rats.

During the early postnatal maturation of the

brain, mitochondrial trafficking is essential not only

for supplying ATP to the neuronal processes but also

for their proper formation, and energy deficits during

this period lead to the impaired neuronal plasticity

[39-43]. We did not detect obvious disruptions in the

mitochondrial trafficking in the brains of OXYS rats

during the early postnatal period. However, signs of

altered neuronal mitochondrial trafficking in the ax-

onal processes were noted: in the hippocampus of

OXYS rats, the number of organelles was slightly low-

er than in Wistar rats (p  =  0.052) at 14 days of age,

and in the prefrontal cortex, it was lower during the

first two weeks but increased at 20 days of age.

No interline differences were found in the mi-

tochondrial content of the neuronal bodies in the

prefrontal cortex during completion of brain matu-

ration (20  days). However, the reduced proportion

of organelles undergoing fusion/fission in OXYS rats

indicates decreased mitochondrial dynamics in these

animals. As in the first week of life, fusion processes

(Mfn2) are reduced in the cerebral cortex of OXYS

rats, while fission (Drp1 and Mfn2/Drp1) is enhanced.

In the cortical neuropil, the number of mitochondria

was higher due to their content in the axonal pro-

cesses. In the hippocampus of OXYS rats during this

period, the number of mitochondria in the neuronal

bodies and neuropil was higher than in Wistar rats,

and according to the assessment of mitochondrial dy-

namics activity, the fusion/fission balance was shifted

toward mitochondrial fusion. As a sign of disrupted

mitochondrial dynamics, we consider the previously

identified [44] increase in the number of mito-

chondria with an unusual phenotype – “mitochon-

dria-on-a-string” (MOAS) – in the processes of cortical

neurons in OXYS rats. Such mitochondria have been

found in the brain neurons of the AD patients and

AD mouse models and are believed to be associated

with incomplete fission [45]. Importantly, the specif-

ic quantity of MOAS in the neuropil of OXYS rats is

most significantly increased – 8 times – at 20 days

MITOCHONDRIA IN DEVELOPING BRAIN 2037

BIOCHEMISTRY (Moscow) Vol. 90 No. 12 2025

of age, during completion of the brain maturation,

when effective axonal mitochondrial trafficking is a

necessary condition for formation of the neuronal

networks.

It is only logically to assume that the identified

structural and functional changes in the mitochondria

of OXYS rats are underpinned by the changes in the

expression of associated genes. Earlier, we analyzed

changes in the transcriptomes of the cerebral cortex

and hippocampus of Wistar and OXYS rats (RNA-seq

data) from the early postnatal period to the age of AD

progression (P3, P10, P20 (P – postnatal day), 5 and

18 months), identifying metabolic pathways and pro-

cesses whose alterations precede and accompany the

disease development in OXYS rats. Notably, the most

significant and comparable differences in the gene

expression and associated processes are observed

during the early postnatal period and at the stage

of pronounced neurodegenerative changes, when

they are comparable between OXYS rats and the AD

patients [16, 18]. Expression of the mitochondria-as-

sociated genes is already altered in OXYS rats of 3

and 10 days of age [18] and at 20 days, during the

“preclinical” period of AD development, and remains

altered during manifestation and progression of the

disease [19].

CONCLUSION

We previously showed that manifestation and

progression of all key signs of AD in OXYS rats – de-

structive changes and neuronal death, synaptic in-

sufficiency, hyperphosphorylation of tau protein, en-

hanced accumulation of Aβ1-42 (Aβ – amyloid beta),

and formation of amyloid plaques in the brain, as well

as memory impairment and learning ability – occur

against the background of increasing dysfunction and

significant decrease in the specific number of mito-

chondria in the neurons of the hippocampus and ce-

rebral cortex [15, 16]. Overall, the results obtained in

this and previous studies showed that as early as the

early postnatal period (from birth to 20 days of age),

OXYS rats exhibit structural and functional changes in

the mitochondria in neurons of the hippocampus and

cerebral cortex, which subsequently increase during

manifestation of AD signs (3-5 months of age) and

their progression (24 months of age). The causes lead-

ing to the accelerated brain aging in OXYS rats and

the development of AD signs in them remain unclear,

but we believe that deviations in formation of the mi-

tochondrial apparatus identified in this study in the

early postnatal period could contribute to the delayed

brain maturation in OXYS rats, promote mitochondri-

al dysfunction, reduce synaptic density, and ultimate-

ly lead to the neuronal death and development of

the early neurodegenerative changes. Thus, we have

shown that mitochondrial dysfunction mediates and/

or possibly even initiates the pathological molecular

cascades of AD development in OXYS rats and could

be considered a predictor of the early development

of the sporadic form of this disease in humans.

Abbreviations

AD Alzheimer’s disease

Contributions

N. A. Stefanova and N. G. Kolosova – concept and su-

pervision of the work; N. A. Muraleva, D. V. Sityaeva,

M. A. Tyumentsev, and N. A. Stefanova – conducting

experiments; N. A. Stefanova and N. G. Kolosova – dis-

cussion of the research results; N. A. Stefanova and

N. G. Kolosova – writing the text; N. G. Kolosova – edit-

ing the article text.

Funding

This work was supported by the federal budget project

FWNR-2022-0016.

Ethics approval and consent to participate

The study was conducted on OXYS and Wistar rats

(control strain) at the Shared Research Facility

“Vivarium of Conventional Animals” of the Institute

of Cytology and Genetics, Siberian Branch of the Rus-

sian Academy of Sciences. Maintenance of animals

(including appropriate facilities, qualified personnel,

and necessary documentation) and all experiments

with animals were carried out in accordance with the

position on the ethics of using animals in research

supported by the Russian Science Foundation, as well

as in accordance with Directive 2010/63/EU of the Eu-

ropean Parliament and the Council of the European

Union of September 22, 2010, and approved by the

Bioethics Commission of ICG SB RAS (no. 85/1 dated

18.06.2021).

Conflict of interest

The authors of this work declare that they have no

conflicts of interest.

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article’s Creative Commons license, unless indicated

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