OXPHOS deficiency activates global adaptation pathways to maintain mitochondrial membrane potential

Liu, Siqi; Liu, Shanshan; He, Baiyu; Li, Lanlan; Li, Lin; Wang, Jiawen; Cai, Tao; Chen, She; Jiang, Hui

doi:10.15252/embr.202051606

Cited by 52 publications

(41 citation statements)

References 92 publications

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“…Together, these results are in good agreement with earlier experiments on Δinh1Δstf1 yeast mitochondria ( Venard et al, 2003 ). Finally, in line with previous studies ( Liu et al, 2021 ), Δinh1Δstf1 strain with depleted mtDNA ( Δinh1Δstf1 rho 0 ) demonstrated an increase in the proliferation rate compared to the control rho 0 strain, although the amplitude of the effect was small ( Figure 3D ).…”

Section: Resultssupporting

confidence: 92%

“…Inhibition of F 1 -subcomplex ATPase activity by Inh1p decreases Δ μ˜ H + in rho 0 yeast mitochondria, whereas mitochondrial Δ μ˜ H + is essential for rho 0 cells proliferation. Indeed, increased INH1 expression decreases the growth rate of rho 0 yeast cells, while INH1 deletion accelerates growth ( Liu et al, 2021 ). Furthermore, while yeast cells with deleted i-AAA protease gene YME1 cannot survive without mtDNA, the Δyme1Δinh1 rho 0 strain proved to be viable.…”

Section: Introductionmentioning

confidence: 99%

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Heterogeneity of Starved Yeast Cells in IF1 Levels Suggests the Role of This Protein in vivo

et al. 2022

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In mitochondria, a small protein IF1 suppresses the hydrolytic activity of ATP synthase and presumably prevents excessive ATP hydrolysis under conditions of energy deprivation. In yeast Saccharomyces cerevisiae, IF1 homologs are encoded by two paralogous genes: INH1 and STF1. INH1 expression is known to aggravate the deleterious effects of mitochondrial DNA (mtDNA) depletion. Surprisingly, no beneficial effects of INH1 and STF1 were documented for yeast so far, and the functions of INH1 and STF1 in wild type cells are unclear. Here, we put forward a hypothesis that INH1 and STF1 bring advantage during the fast start of proliferation after reentry into exponential growth from post-diauxic or stationary phases. We found that yeast cells increase the concentration of both proteins in the post-diauxic phase. Post-diauxic phase yeast cells formed two subpopulations distinct in Inh1p and Stf1p concentrations. Upon exit from the post-diauxic phase cells with high level of Inh1-GFP started growing earlier than cells devoid of Inh1-GFP. However, double deletion of INH1 and STF1 did not increase the lag period necessary for stationary phase yeast cells to start growing after reinoculation into the fresh medium. These results point to a redundancy of the mechanisms preventing uncontrolled ATP hydrolysis during energy deprivation.

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Section: Resultssupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Heterogeneity of Starved Yeast Cells in IF1 Levels Suggests the Role of This Protein in vivo

et al. 2022

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“…In conclusion, since ATP production by mitochondrial OXPHOS is impaired in many human diseases involving over 150 genes ( Liu et al, 2021 ), including Parkinson’s disease and schizophrenia ( Bergman and Ben-Shachar, 2016 ; López-Gallardo et al, 2011 ; Zhu and Wang, 2017 ), as well as during aging ( Olgun and Akman, 2007 ) and neurodegeneration ( Koopman et al, 2013 ), the results presented here suggest a mechanistic link to peroxisomal dysfunction in human mitochondrial disorders. Further explorations of this yeast model would provide important insights regarding interorganellar communication, interplay, and dynamics, while also shedding light on human disease.…”

Section: Discussionmentioning

confidence: 63%

OXPHOS deficiencies affect peroxisome proliferation by downregulating genes controlled by the SNF1 signaling pathway

Farré

Carolino

Devanneaux

et al. 2022

eLife

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How environmental cues influence peroxisome proliferation, particularly through organelles, remains largely unknown. Yeast peroxisomes metabolize fatty acids (FA), and methylotrophic yeasts also metabolize methanol. NADH and acetyl-CoA, produced by these pathways enter mitochondria for ATP production and for anabolic reactions. During the metabolism of FA and/or methanol, the mitochondrial oxidative phosphorylation (OXPHOS) pathway accepts NADH for ATP production and maintains cellular redox balance. Remarkably, peroxisome proliferation in Pichia pastoris was abolished in NADH shuttling- and OXPHOS mutants affecting complex I or III, or by the mitochondrial uncoupler, 2,4-dinitrophenol (DNP), indicating ATP depletion causes the phenotype. We show that mitochondrial OXPHOS deficiency inhibits expression of several peroxisomal proteins implicated in FA and methanol metabolism, as well as in peroxisome division and proliferation. These genes are regulated by the Snf1 complex (SNF1), a pathway generally activated by a high AMP/ATP ratio. In OXPHOS mutants, Snf1 is activated by phosphorylation, but Gal83, its interacting subunit, fails to translocate to the nucleus. Phenotypic defects in peroxisome proliferation observed in the OXPHOS mutants, and phenocopied by the Dgal83 mutant, were rescued by deletion of three transcriptional repressor genes (MIG1, MIG2 and NRG1) controlled by SNF1 signaling. Our results are interpreted in terms of a mechanism by which peroxisomal and mitochondrial proteins and/or metabolites influence redox and energy metabolism, while also influencing peroxisome biogenesis and proliferation, thereby exemplifying interorganellar communication and interplay involving peroxisomes, mitochondria, cytosol and the nucleus. We discuss the physiological relevance of this work in the context of human OXPHOS deficiencies.

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“…In conclusion, since ATP production by mitochondrial OXPHOS is impaired in many human diseases involving over 150 genes [103], including Parkinson's disease and schizophrenia [104][105][106], as well as during aging [107] and neurodegeneration [108], the results presented here provide a clear mechanistic link to peroxisomal dysfunction in human mitochondrial disorders.…”

Section: Working Model For Interorganellar Control Of Peroxisome Dynamicsmentioning

confidence: 64%

“…Since SNF1/AMPK activation in both yeast and mammalian cells upregulates glycolysis, gluconeogenesis and mitochondrial biogenesis, while repressing ATP consumption [103,109], it makes sense that this would also enhance peroxisome proliferation because peroxisomes house several glyoxylate pathway enzymes that are necessary for gluconeogenesis [110]. Likewise, since peroxisomal metabolites (like NADH and products of the b-oxidation of very long chain FA) influence mitochondrial ATP production [111], these studies also explain how diseases affecting peroxisome biogenesis can impair mitochondria.…”

Section: Working Model For Interorganellar Control Of Peroxisome Dynamicsmentioning

confidence: 99%

OXPHOS deficiencies affect peroxisome proliferation by downregulating genes controlled by the SNF1 signaling pathway

Farré

Carolino

Devanneaux

et al. 2021

Preprint

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How environmental cues influence peroxisome proliferation, particularly through other organelles, remains largely unknown. Yeast peroxisomes metabolize all fatty acids (FA), and methylotrophic yeasts also metabolize methanol. NADH and acetyl-CoA, the products of these pathways enter mitochondria for ATP production, and for anabolic reactions. During the metabolism of FA and/or methanol, the mitochondrial oxidative phosphorylation (OXPHOS) pathway accepts NADH for ATP production and maintains cellular redox balance. Remarkably, peroxisome proliferation in Pichia pastoris was abolished in NADH shuttling and OXPHOS mutants affecting complex I or III, or by the mitochondrial uncoupler, 2,4-dinitrophenol (DNP), indicating ATP depletion causes the phenotype. We show that mitochondrial OXPHOS deficiency inhibits the expression of several peroxisomal proteins implicated in FA and methanol metabolism, as well as in peroxisome division and proliferation. These genes are regulated by the Snf1 complex (SNF1), a pathway generally activated by high AMP and low ATP. Consistent with this mechanism, in OXPHOS mutants, Snf1 is activated by phosphorylation, but Gal83, its interacting subunit, fails to translocate to the nucleus. Phenotypic defects in peroxisome proliferation observed in the OXPHOS mutants, and phenocopied by the Δgal83 mutant, were rescued by deletion of three transcriptional repressor genes (MIG1, MIG2 and NRG1) controlled by SNF1 signaling. We uncovered here the mechanism by which peroxisomal and mitochondrial metabolites influence redox and energy metabolism, while also influencing peroxisome biogenesis and proliferation, thereby exemplifying interorganellar communication and interplay involving peroxisomes, mitochondria, cytosol and the nucleus. We discuss the physiological relevance of this work in view of human OXPHOS deficiencies.

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OXPHOS deficiency activates global adaptation pathways to maintain mitochondrial membrane potential

Cited by 52 publications

References 92 publications

Heterogeneity of Starved Yeast Cells in IF1 Levels Suggests the Role of This Protein in vivo

Heterogeneity of Starved Yeast Cells in IF1 Levels Suggests the Role of This Protein in vivo

OXPHOS deficiencies affect peroxisome proliferation by downregulating genes controlled by the SNF1 signaling pathway

OXPHOS deficiencies affect peroxisome proliferation by downregulating genes controlled by the SNF1 signaling pathway

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