Article

ISSN 0006-2979, Biochemistry (Moscow), 2023, Vol. 88, Nos. 12-13, pp. 1997-2006 © Pleiades Publishing, Ltd., 2023.

Published in Russian in Biokhimiya, 2023, Vol. 88, No. 12, pp. 2387-2398.

1997

REVIEW

Role of Mitochondrial DNA in Yeast Replicative Aging

Aglaia V. Azbarova

1,2

and Dmitry A. Knorre

1,a

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

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

e-mail: knorre@belozersky.msu.ru

Received August 23, 2023

Revised November 13, 2023

Accepted November 15, 2023

Abstract— Despite the diverse manifestations of aging across different species, some common aging features and underlying

mechanisms are shared. In particular, mitochondria appear to be among the most vulnerable systems in both metazoa and

fungi. In this review, we discuss how mitochondrial dysfunction is related to replicative aging in the simplest eukaryotic

model, the baker’s yeast Saccharomyces cerevisiae. We discuss a chain of events that starts from asymmetric distribution

of mitochondria between mother and daughter cells. With age, yeast mother cells start to experience a decrease in mito-

chondrial transmembrane potential and, consequently, a decrease in mitochondrial protein import efficiency. This induces

mitochondrial protein precursors in the cytoplasm, the loss of mitochondrial DNA (mtDNA), and at the later stages–

cell death. Interestingly, yeast strains without mtDNA can have either increased or decreased lifespan compared to the

parental strains with mtDNA. The direction of the effect depends on their ability to activate compensatory mechanisms

preventing or mitigating negative consequences of mitochondrial dysfunction. The central role of mitochondria in yeast

aging and death indicates that it is one of the most complex and, therefore, deregulation-prone systems in eukaryotic cells.

DOI: 10.1134/S0006297923120040

Keywords: yeast, development, aging, mitochondrial DNA, mitochondrial dysfunction

Abbreviations: ERC, extrachromosomal rDNA circle; mtDNA, mitochondrial DNA; OxPhos, oxidative phosphorylation;

RLS,replicative lifespan.

* To whom correspondence should be addressed.

INTRODUCTION

Aging is the process characterized by a decrease in

fertility and an increase in mortality over time [1], a phe-

nomenon that inevitably emerges in the process of living

systems evolution. This is attributed to the fact that nat-

ural selection diminishes in the post-production period,

as it primarily affects genes and traits associated with

reproduction. Consequently, as an organism generates

more offspring, the impact of natural selection on traits

(and the corresponding genes) that emerge after repro-

duction begins to wane [2, 3]. This is applicable to mi-

croorganisms as well, including bacteria and unicellular

fungi. Bacterial and yeast species that divide asymmetri-

cally– those that produce a mother cell and a daughter

cell of differing sizes– usually exhibit aging [4-7].

The baker’s yeast, Saccharomyces cerevisiae, is the

most extensively studied unicellular organism where ag-

ing has been described [8-10]. Investigations into yeast

aging mechanisms have expanded our understanding of

the fundamental principles of aging. Moreover, yeast

aging studies have facilitated the identification of targe-

table systems that, upon intervention, can lead to lifes-

pan extension. A significant advantage of baker’s yeast

over other model organisms is the high proliferation

rate of yeast cells. Additionally, it is relatively easy to

produce genetically stable mutant yeast cell lines, which

are instrumental in identifying gene and protein func-

tions [11]. Presently, several collections of yeast mutant

strains are available, these collections have been utilized

to conduct genetic screenings aimed at discov ering lon-

gevity genes [12, 13]. For example, caloric restriction

dietary mimetics, including resveratrol, were identified

using the yeast aging model [14]. The efficacy of these

mimetics was later confirmed in animal studies [15].

A screening of mutations altering S. cerevisiae lifespan

revealed 238 genes whose deletion increases it [16].

These genes comprised orthologs of genes whose mu-

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BIOCHEMISTRY (Moscow) Vol. 88 Nos. 12-13 2023

Fig. 1. Two scenarios of replicative aging in yeast. Approximate replicative ages are based on the literature cited in the text.

tations altered the lifespan of the nematodes Caenor-

habditis elegans [16]. The results of this screening were

enriched with genes encoding tricarboxylic acid cycle

enzymes and proteins required for mitochondrial pro-

tein translation, including mitochondrial ribosome pro-

tein components [16]. In a separate study, the authors

demonstrated that deleting yeast orthologs of nematode

aging genes increased, rather than decreased, the lifes-

pan of yeast [17]. Taken together, these results suggest

a conservation of aging mechanisms among eukaryotes.

The aging process of baker’s yeast S. cerevisiae is

typically defined not by chronological time but by the

number of daughter cells a mother cell generates. There-

fore, it is usually referred to as replicative aging [18]

(Fig.1). Accordingly, the number of daughter cells that

a mother cell can produce before its death is termed the

“replicative lifespan”(RLS). A single yeast mother cell

can only generate a limited number of daughter cells,

usually ranging between 15 and 25 [19]. Meanwhile, the

first aging manifestation in the yeast mother cell, such as

changes in the expression of stress response genes, oc-

curs after the formation of the first few buds [20].

As yeast cells age, they undergo deregulation in

gene expression and protein biogenesis. This process

results in disproportion of subunits in protein com-

plexes, such as vacuolar ATPase, in replicatively old

yeast cells [21]. In recent years, advancements in mi-

crofluidics techniques have facilitated the examination

of replicative aging at the individual cell level [22,23].

The aging trajectory of each individual cell is predeter-

mined during the initial cell cycles, leading to one of

two scenarios. Though both scenarios inevitably result

in cell death, the causes of cell viability loss differ be-

tween them [24].

The first scenario is characterized by the loss of

chromatin silencing. This is evidenced by the elevated

expression of rDNA-GFP, a GFP gene integrated into the

non-transcribed rRNA spacer region. Yeast cells aging

through this first scenario maintain a relatively consis-

tent cell cycle duration throughout their lifetime up to

their late life. However, during the last few cell cycles,

which precedes death, such yeast cells form elongated

daughter cells, as depicted in Fig.1.

The second scenario correlates with an increased cell

cycle length during early life stages and the production

of rounded daughter cells. Moreover, in yeast cells aged

under the second scenario, a deficiency of heme is ob-

served [25]. Given that the final stages of heme synthesis

occur within mitochondria, and a lack of heme leads to

mitochondrial dysfunction [26], the aging via this sce-

nario is linked to mitochondrial dysfunction. The death

of yeast cells is preceded by a decrease in Leu4-GFP

levels. Leu4p, or alpha-isopropylmalate synthase, is a

crucial part of the leucine biosynthesis pathway; hence,

a reduction in Leu4p triggers leucine deficiency in older

cells. The second aging scenario is linked to increased

expression of HSP104, a gene that encodes the cytosolic

heat shock protein, Hsp104p [27]. Hsp104p binds and

temporarily stores mitochondrial protein precursors in

the cytoplasm [28], whereas increased concentration of

Hsp104p is a hallmark of the accumulation of unfolded

proteins [29]. Recently, the information about the de-

scribed above scenarios inspired the creation of a genetic

oscillator designed to make yeast cells alternate between

these two aging trajectories, thereby boosting their lifes-

pan by 82% [30].

Replicative aging in yeast can be considered as a

deterministic developmental program that progresses

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BIOCHEMISTRY (Moscow) Vol. 88 Nos. 12-13 2023

along one of at least two possible trajectories (Fig.1).

Deregulation of certain cellular systems restrict yeast

lifespan while concurrently the same systems contrib-

ute to the longevity of multicellular organisms [17]. One

of these yeast aging trajectories is likely associated with

mitochondrial dysfunction. In this review, we discuss

the causal relationship between mitochondrial dysfunc-

tion and other replicative aging manifestations in yeast.

MITOCHONDRIAL DYSFUNCTION

IN YEAST REPLICATIVE AGING

The division of baker’s yeast cells is highly asym-

metrical, resulting in mother and daughter cells of dif-

fering sizes and varying concentrations of certain pro-

teins [31]. This protein content asymmetry is primarily

due to diffusion limitations, which restrict the transport

of large cellular structures, such as large protein aggre-

gates and the organelles harboring them, between the

cells [32]. Moreover, the protein aggregates and cell or-

ganelles are actively transported and can be selectively

anchored in either the mother or daughter cell cortex

[33,34]. The transport of mitochondria from mother to

daughter cells is facilitated by the actin cytoskeleton and

the myosin protein, Myo2p [35]. These cytoskeleton

components anchor the mitochondria with the mean of

mitochondrial outer membrane protein, Mmr1p [36].

Concurrently, the Num1p and Mfb1p proteins ensure

that a portion of the mitochondria remain at the pole of

the mother cell [37, 38]. This active transport and se-

lective retention of mitochondria make it possible to

distribute them between the mother and daughter cells.

This process primarily sends the most functional mito-

chondria to the daughter cell, while ensuring that the

mother cell retains a portion of functional mitochon-

dria, along with the damaged ones [39].

The asymmetric distribution of mitochondria be-

tween mother and daughter cells results in accumula-

tion of mitochondria with oxidized matrix molecules in

the mother cell compared to the mitochondria passed

on to the daughter cell. This is evidenced by the redox-

sensitive fluorescent proteins targeted towards the mito-

chondrial matrix [40, 41]. If the mitochondria are het-

erogeneous, the daughter cell is more likely to inherit

functional mitochondria, while the mother cell retains

the non-functional ones [39]. However, the mechanisms

behind the selectivity of mitochondrial anchoring and

transport remain unclear.

Mitochondrial dysfunction begins to manifest in the

mother cell after several consecutive rounds of asymmet-

rical divisions. Specifically, during the first ten cell cy-

cles, transmembrane potential of the mother cell mito-

chondria decreases [42], and the mitochondrial network

collapses [42, 43]. Factors such as protonophores [44] and

oxidative stress [45, 46] can induce mitochondrial frag-

mentation. This leads to the assumption that age-related

mitochondrial fragmentation is induced by age-depen-

dent mitochondrial depolarization. Studies have shown

that the deletion of DNM1, a gene that encodes the

Dnm1p protein, which mediates mitochondrial fission,

extends the replicative lifespan of yeast [47]. Thus, it can

be concluded that mitochondrial fragmentation plays

acausative role in detrimental processes in aging cells,

and it cannot be considered as a mere side effect of the

depolarization.

Furthermore, the age-dependent decrease in mi-

tochondrial transmembrane potential(ΔΨ) contributes

to a diminished efficiency of protein import into mito-

chondria [48]. While protein import through the outer

membrane does not depend on the ΔΨ, protein trans-

location through the inner membrane stops when ΔΨ is

dissipated [48].

The inhibition of protein import into mitochon-

dria has two unfavorable outcomes for the cell. Firstly,

it can cause a deficiency in proteins vital for mitochon-

drial DNA(mtDNA) replication, as well as mitochon-

drial transcription and translation. It is noteworthy that

yeast aging correlates with a drop in Mip1p levels, a mi-

tochondrial DNA polymerase, an enzyme indispensable

for mtDNA replication [49]. Interestingly, increased ex-

pression of the TOM70 gene, encoding a component of

the translocase of the outer mitochondrial membrane

(TOM) complex, may partially offset this effect by ac-

tivating protein import [49]. This finding suggests that

compromised protein import is a contributing factor to

replicative aging in yeast. Eventually, the inhibition of

mitochondrial protein import culminates in the loss of

mtDNA in replicatively aged cells [50] (Fig.1).

Secondly, the inhibition of protein import into

mitochondria results in the accumulation of the mito-

chondrial protein precursors in the cytoplasm. These

precursors are known to be toxic to the cell. For exam-

ple, the expression of “clogger” proteins, which block

the mitochondrial protein import system, inhibits the

growth of yeast cells [28]. Although S. cerevisiae cells can

survive without mtDNA and oxidative phosphorylation

(OxPhos) by relying on glycolysis, the deletion of TIM-

(mitochondrial inner membrane translocase) or TOM-

complex genes are usually lethal [51].

We propose that these two unfavorable phenome-

na– a reduction in the concentration of essential pro-

teins in the mitochondria and proteotoxic stress induced

by mitochondrial protein precursors in the cytosol –

contribute to an extended cell cycle duration and, even-

tually, cell death. To our knowledge, there are no direct

experimental assessments of the mitochondrial contri-

bution to these two yeast aging scenarios. However, the

second scenario is associated with mitochondrial net-

work fragmentation [25] and a decrease in mitochon-

drial membrane potential, as evidenced by a reduction

in DiOC6 staining of aging cells [27]. This implies that

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BIOCHEMISTRY (Moscow) Vol. 88 Nos. 12-13 2023

mitochondrial dysfunction is more likely associated with

the second scenario.

BIDIRECTIONAL EFFECT

OF MITOCHONDRIAL DNA DEPLETION

ON YEAST REPLICATIVE LIFESPAN

The mitochondrion, a semi-autonomous cellular

organelle found in most eukaryotic species, retains its

own DNA. This DNA encodes components of mito-

chondrial translation systems, as well as some respirato-

ry chain proteins [52]. Therefore, mutations in mtDNA

or its complete disappearance (denoted as rho

) result in

the loss of mitochondrial capacity to perform OxPhos.

In certain laboratory strains, such as YPK9, the

elimination of mitochondrial DNA (rho

mutation) trig-

gers an increase in RLS [53-57]. However, this effect is

not universal; in some strains, the rho

mutations have

the opposite effect [58], or no effect [53]. An example

of this can be observed in the W303-1A strain, which

is frequently used for studying OxPhos in yeast [53].

Furthermore, removal of mtDNA in strains based on

BY4742– the genetic background for yeast mutant col-

lections– does not induce an increase in RLS [59,60].

We propose that the contrasting effects of the rho

mutation can be attributed to the varying responses

of different strains to mitochondrial dysfunction [53].

Thecomplete depletion of mitochondrial DNA in yeasts

alters both gene expression levels and protein concen-

trations [61-63]. Notably, rho

mutation activates retro-

grade signaling cascade, which in turn activates genes

that encode glycolysis and the glyoxylate cycle enzymes

[61, 64]. This process enables cells to adapt their met-

abolic functions to conditions where OxPhos is unfeasi-

ble and reactions linked to respiration, such as succinate

oxidation, are blocked.

At the same time, laboratory strains can react differ-

ently to the loss of mtDNA. For instance, the W303-1A

strain, following the complete depletion of mtDNA,

does not increase the expression of the CIT2 gene, en-

coding citrate-synthase localized in peroxisomes [65].

Conversely, YPK9 rho

cells, which exhibit a high RLS,

upregulate this gene [53]. Furthermore, different labora-

tory strains can vary in rDNA array length [66], which

is positively correlated with yeast RLS [67]. This cor-

relation is attributed to the regulation of the histone

deacetylase gene SIR2. Sir2p limits the formation of

ex trachromosomal rDNA circles (ERCs), identified as

one of the factors contributing to aging. Concur rently,

upstream activation factors (UAFs) bind to chromo-

somal rDNA and, when not bound, inhibit Sir2p. As

a result, strains with a shorter rDNA array length pos-

sess a higher number of free UAFs, which inhibit Sir2p,

induce ERC formation. ERCs accumulate in older

cells, disrupting chromatin silencing and increasing

the probability of cell death with age, leading to de-

creased RLS [67].

We suggest that the lifespan of yeast strains with

shorter rDNA array lengths is primarily constrained by

the activity of SIR2, the formation of ERCs, and the

prevalence of aging through the second scenario. There-

fore, mitochondrial dysfunction does not pose a limita-

tion to the RLS in these strains. Conversely, in strains

with a longer rDNA array, aging predominantly proceeds

via the second scenario, which is linked to mitochon-

drial function. In this context, mitochondrial dysfunc-

tion accelerates the aging process and shortens RLS.

The strains’ variability in the consequences of

mtDNA depletion could also be explained by the dy-

namics of the cell adaptation to mtDNA loss, a pro-

cess requiring tenth of generations [68]. Notably, new-

ly formed rho

cells exhibit a reduced lifespan, while

adapted to the absence of mtDNA rho

cells demon-

strate an extended lifespan in comparison to the paren-

tal strain[68]. It could be hypothesized that this adap-

tation process unfolds at different speeds and follows

distinct pathways in various laboratory strains. This, in

turn, contributes to the observed variability in the im-

pact of the rho

mutation on RLS.

The loss of mtDNA could have differential effects

on the two aging scenarios previously outlined. While

itmay accelerate aging in one scenario, it could poten-

tially inhibit the aging process in the other. For instance,

in the context of the second scenario, the rho

mutation

could help yeast cells in pre-adapting to the detrimen-

tal processes of aging, such as disruption of heme bio-

genesis. The variable proportions of cells in laboratory

strains, which are presumed to age following one sce-

nario or another, may contribute to the uncertainty re-

garding the effect of mtDNA loss on RLS.

THE ROLE OF NUCLEAR-ENCODED

MITOCHONDRIAL PROTEINS

IN YEAST REPLICATIVE LONGEVITY

The yeast mitochondrial proteome comprises ~900

proteins, the vast majority of these proteins are encoded

within the nucleus and are imported into the mitochon-

dria from the cytoplasm [69]. Therefore, mitochondrial

dysfunction can arise not only from the loss of mtDNA

but also from the inactivation of nuclear genes that en-

code these proteins. In a study involving whole-genome

sequencing of an entire yeast knockout collection, it was

revealed that the deletion of 129 out of roughly 5000

nonessential genes leads to the loss of mtDNA [70].

Intriguingly, several of these genes were also identified in

a screen designed to uncover genes whose deletion results

in an increased RLS of yeast [16]. This overlap is not like-

ly to be random and suggests an interconnection between

mitochondrial DNA maintenance and RLS (Fig.2).

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BIOCHEMISTRY (Moscow) Vol. 88 Nos. 12-13 2023

Fig. 2. The Venn diagram illustrates the intersection of two gene sets in yeast S.cerevisiae. One set includes genes whose deletion leads to mtDNA

loss (Puddu etal. [70]), the other set comprises genes whose deletion results in an increased replicative lifespan (McCormick etal. [16]). The prob-

ability of a random overlap of 17 or more genes between these two samples is less than 0.1%.

However, it is important to note that not all genes,

whose deletion results in mtDNA loss, necessarily lead

to an increased lifespan. Among the genes encoding for

mitochondrial proteins, whose deletion concurrently

enhances yeast RLS, one category stands out: the genes

encoding components of the mitochondrial ribosome.

The Venn diagram depicted in Fig. 2 illustrates that

the deletion of MRPL33, MRPL40, MRPL49, IMG1,

and IMG2 genes, which encode mitochondrial ribo-

somal proteins, leads to an increase in RLS. Further-

more, the deletion of another ribosomal protein gene,

MRPL25, renders cell resistance to pro-oxidants and

increases RLS, with the maximum lifespan of the de-

letion strain reaching 60 [71]. Additionally, the deletion

of the SOV1 gene, which is essential for mitochondrial

ribosome assembly, has also been observed to increase

yeast RLS [72].

The mitochondrial ribosome cannot be assembled

irrespective of the reasons causing mtDNA loss because

mtDNA encodes mitochondrial rRNA subunits [73],

making it impossible for mitochondrial ribosomes to

assemble in the absence of mtDNA. Thus, what makes

protein components of mitochondrial ribosomes special

remains uncertain. However, the import mechanism of

mitochondrial ribosome proteins (MRPs) diverges from

that of other mitochondrial proteins. A significant num-

ber of MRPs lack a distinctive mitochondrial address

sequence, a phenomenon attributed to the conservative

nature of their function, including the N-terminal re-

gion of these proteins [74]. Thus, deleting MRP genes

could affect the mitochondrial import machinery in a

unique way, distinct from the effect caused by the de-

letion of other mitochondrial proteins harboring a con-

ventional N-end mitochondrial address. For instance,

the deletion of MRP genes could potentially unburden

a specific set of accessory TOM proteins. An alternative

explanation for the unique phenotype associated with

MRP deletion could be that the absence of rRNA in the

mitochondria of rho

cells can increase toxicity of some

other MRP proteins, consequently accelerating the aging

process in yeast mother cells. Caballero etal. suggested

that the disappearance of certain mitochondrial trans-

lation machinery components could result in acquiring

novel signaling functions by the remaining components.

These functions could be related to chromatin silencing,

potentially leading to an extended lifespan [72]. This

hypothesis aligns with observations made regarding the

Cbs2p protein, which possesses dual cytosol and mito-

chondrial localization. This protein appears to be es-

sential for the life-extension effect of the mitochondrial

translation activator gene, CBS1, deletion [72].

While the deletion of certain nuclear-encoded mi-

tochondrial protein genes increases RLS, the deletion

of some other genes substantially diminishes it. For in-

stance, deleting the MIP1 gene, which encodes mito-

chondrial DNA polymerase, results in a reduced yeast

lifespan [72]. MtDNA replication is impossible without

Mip1p. Similarly, a decrease in RLS is also noted upon

the deletion of the COX4, COX7 genes [72, 75], and cyto-

chrome c heme lyase gene CYC3 [76]. COX genes encode

complexIV subunits of the respiratory chain. Their ab-

sence disrupts OxPhos, thereby rendering the utilization

AZBAROVA, KNORRE2002

BIOCHEMISTRY (Moscow) Vol. 88 Nos. 12-13 2023

of non-fermentable carbon sources impossible [77].

Thedeletion of TOM70, a gene that encodes a compo-

nent of the TOM complex, reduces RLS [49]. Similarly,

RLS is decreased upon the deletion of PIM1, a gene en-

coding mitochondrial matrix protease [78]. We propose

that mitochondrial dysfunction may accelerate aging by

inflating the number of cells that age by the second sce-

nario. Meanwhile, the second scenario is characterized

by a shortened yeast RLS, in comparison to the first

scenario, which is associated with deregulation of chro-

matin silencing [25].

Mitochondrial dysfunction can be induced by mi-

tochondrial inhibitors such as antimycin A or oligomy-

cin D, as well as protonophores, which dissipate mi-

tochondrial membrane potential. These interventions,

similar to the rho

mutation, exhibit bidirectional effects

on RLS that can vary based on other factors [76,79].

For instance, on the one hand, the “weak” protono-

phore dinitrophenol, when applied at a concentration

of 5 mM, has been shown to slightly increase RLS [79].

This effect was likely mediated through the activation

of the Rtg mitochondria-to-nucleus signaling pathway.

Meanwhile, it has been shown that protonophores ac-

tivate the PDR5 gene, a known target of the Rtg path-

way[80], and the Rtg pathway can trigger adaptive re-

sponses that extend the RLS of yeast [81].

On the other hand, the “strong” protonophore cy-

anide-p-trifluoromethoxy phenylhydrazone, FCCP, re-

sults in a significant decrease in RLS of BY4741 cells[82].

How can protonophores contribute to this decrease in

RLS? The diminished mitochondrial transmembrane

potential, induced by protonophores, can exhibit selec-

tive toxicity towards cells with limited capacity to gen-

erate ΔΨ. Indeed, the protonophores are particularly

toxic to rho

cells, where the ΔΨ is generated by the ad-

enine nucleotide translocator, which appears to be not

very effective [83, 84]. As the replicative age of a yeast

cell advances, the likelihood of total loss of mtDNA and

respiratory activity elevates. Therefore, high concentra-

tions of protonophores might be selectively detrimental

to older cells relative to younger ones, thereby reducing

RLS [83,84].

CONCLUSIONS

We hypothesize the following chain of events in

aging yeast cells. The asymmetric distribution of mi-

tochondria results in the accumulation of dysfunction-

al mitochondria in the mother cell. As a result, mito-

chondrial dysfunction emerges during the early stages of

replicative aging. With age, the yeast cells experience a

deficiency in nucleus-encoded mitochondrial proteins.

This deficiency subsequently induces mutations or a

complete loss of mtDNA. At the same time, toxic mito-

chondrial protein precursors are accumulated within the

cytoplasm. Furthermore, as yeast cells age, they increas-

ingly depend on oxidative metabolism, in contrast to

younger cells that rely more heavily on glycolysis. Yeast

replicative aging is associated with upregulated pentose

phosphate pathway, tricarboxylic acid cycle and glycer-

ol biosynthesis pathways, alongside with a decrease in

cellular ATP concentration [85]. Thus, while mitochon-

drial dysfunction increases with age, the sequential met-

abolic adjustments in the cell render it increasingly re-

liant on OxPhos. This seeming paradox may contribute

to a diminished growth rate of the old cells, ultimately

leading to cell death.

The notion that mitochondrial dysfunction decreas-

es viability of older cells implies that cells with initially

compromised OxPhos may have a shortened lifespan.

Furthermore, the way how yeast cells adapt to mito-

chondrial dysfunction, such as activating mitochondria-

to-nucleus pathway targets, seems to be a crucial fac-

tor for yeast longevity. Taken together, the yeast aging

model reveals a vulnerable system within eukaryotic

cells, which appears susceptible to deregulation. This

system, the coordination mechanism between the mito-

chondria and the nucleus, is an intricate machinery that

has evolved over a billion years since the symbiogenesis

of archaea and mitochondrial ancestors.

Contributions. A.A. and D.K. contributed to the

analysis of the literature and the writing of the text.

D.K. prepared the illustrations.

Funding. This work was supported by the Russian

Science Foundation, grant no.22-14-00108.

Ethics declarations. The authors declare no conflict

of interest. This article does not describe any research

involving humans or animals as subjects.

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