Mitochondrial retrograde signaling inhibits the survival during prolong S/G2 arrest in<i>Saccharomyces cerevisiae</i>

Zyrina, Anna N.; Sokolov, Svyatoslav S.; Knorre, Dmitry A.; Severin, Fedor F.

doi:10.18632/oncotarget.6406

Cited by 11 publications

(7 citation statements)

References 49 publications

(59 reference statements)

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“…Together, these results demonstrate that ρ 0 cells exhibit slow growth characterized by a delayed G1-to-S transition, and thus confirm previous observations of an impaired G1 exit upon mtDNA loss that has been termed the mtDNA inheritance checkpoint (Crider et al, 2012; Veatch et al, 2009; Zyrina et al, 2015). However, the factors mediating the mtDNA inheritance checkpoint, as well as the initial signal that triggers the cell cycle defect, have not been uncovered.…”

Section: Resultssupporting

confidence: 89%

“…In addition to preventing cellular respiration and decreasing ΔΨm, mtDNA loss promotes nuclear DNA instability and defective cell cycle progression that manifests as an accumulation of cells in G1 phase (Veatch et al, 2009;Zyrina et al, 2015). In an elegant study, Veatch et al showed these two effects to be separate from each other: while the nuclear DNA instability in mtDNA-depleted cells was driven by defective Fe-S cluster protein assembly, the mechanism(s) underlying the cell cycle defect were not uncovered but were found to be independent of Fe-S metabolism (Veatch et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Mitochondrial membrane potential acts as a retrograde signal to regulate cell cycle progression

Gorospe

Curbelo

Carvalho

et al. 2022

Preprint

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Mitochondria are central to numerous anabolic and catabolic pathways whereby mitochondrial dysfunction has a profound impact on metabolism and can manifest in disease. The consequences of mitochondrial dysfunction can be ameliorated by adaptive responses that rely on mito-cellular crosstalk to communicate mitochondrial distress to the rest of the cell. Such mito-cellular signaling slows cell cycle progression in mitochondrial-DNA deficient (ρ0) Saccharomyces cerevisiae cells, but the initial trigger and the pathway mediating the response has remained unknown. Here, we show that decreased mitochondrial membrane potential (ΔΨm) acts as the initial signal of mitochondrial stress that delays G1-to-S phase transition in both ρ0 and control cells. Accordingly, experimentally increasing ΔΨm was sufficient to restore timely cell cycle progression in ρ0 cells. Neither the RTG retrograde pathway nor central DNA damage checkpoint kinases were involved in mediating this form of mito-cellular communication. The identification of ΔΨm as a novel regulator of cell cycle progression may have implications for disease states involving mitochondrial dysfunction.

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Section: Resultssupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

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Mitochondrial membrane potential acts as a retrograde signal to regulate cell cycle progression

Gorospe

Curbelo

Carvalho

et al. 2022

Preprint

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“…Such growth is associated with prolonged cell cycle delay in G2-phase 89. We have also shown that signaling mediated by Rtg-proteins contributes to the severity of S-phase arrest induced by telomere dysfunction 90. At the same time, early studies showed that cell cycle arrest does not prevent mtDNA overreplication 1819.…”

Section: Retrograde Signaling and Cell Cyclementioning

confidence: 91%

How do yeast sense mitochondrial dysfunction?

et al. 2016

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Apart from energy transformation, mitochondria play important signaling roles. In yeast, mitochondrial signaling relies on several molecular cascades. However, it is not clear how a cell detects a particular mitochondrial malfunction. The problem is that there are many possible manifestations of mitochondrial dysfunction. For example, exposure to the specific antibiotics can either decrease (inhibitors of respiratory chain) or increase (inhibitors of ATP-synthase) mitochondrial transmembrane potential. Moreover, even in the absence of the dysfunctions, a cell needs feedback from mitochondria to coordinate mitochondrial biogenesis and/or removal by mitophagy during the division cycle. To cope with the complexity, only a limited set of compounds is monitored by yeast cells to estimate mitochondrial functionality. The known examples of such compounds are ATP, reactive oxygen species, intermediates of amino acids synthesis, short peptides, Fe-S clusters and heme, and also the precursor proteins which fail to be imported by mitochondria. On one hand, the levels of these molecules depend not only on mitochondria. On the other hand, these substances are recognized by the cytosolic sensors which transmit the signals to the nucleus leading to general, as opposed to mitochondria-specific, transcriptional response. Therefore, we argue that both ways of mitochondria-to-nucleus communication in yeast are mostly (if not completely) unspecific, are mediated by the cytosolic signaling machinery and strongly depend on cellular metabolic state.

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“…This is surprising, because for their energy needs cancer cells tend to rely on glycolysis instead of oxidative phosphorylation. Our study with model eukaryotic cells – baker's yeast – provides an explanation: we found that the loss of mtDNA activates a signaling cascade that tightens the S-phase arrest of the cells caused by inactivation of telomerase [ 6 ]. Importantly, this effect was not due to alterations in ATP supply.…”

mentioning

confidence: 99%