Oxphos Deficiency Activates Global Adaptations To Maintain Mitochondrial Membrane Potential

Oxidative phosphorylation(OXPHOS)generates mitochondrial membrane potential(??m)to synthesize ATP and drive protein import and metabolite transportation.Reduction of ??m caused by OXPHOS dysfunction is a life-threatening condition because ??m maintains the synthesis of iron-sulfur cluster(ISC),an indispensable cofactor for many house-keeping enzymes.Decreased ??m activates adaptive responses to rewire metabolism,remove depolarized mitochondria,and degrade unimported precursor proteins.However,it is unknown whether there is protective mechanism to maintain ??m.Here we have analyzed the adaptive changes of transcriptome and mitochondrial proteome in yeast and mouse models to understand whether and how cells maintain ??m under OXPHOS deficiency.Yeast oxidative phosphorylation mutants deficient in complex ?,?,?,and mtDNA respectively,have graded reduction of ??m and proliferation rates.Extensive Omics analyses of these mutants show that accompanying ??m reduction,these mutants progressively activate adaptive responses,including transcriptional downregulation of ATP synthase inhibitor Inh1 and OXPHOS subunits,Puf3-mediated upregulation of import receptor Mia40 and global mitochondrial biogenesis,Snf1/AMPK-mediated upregulation of glycolysis and repression of ribosome biogenesis,and transcriptional upregulation of cytoplasmic chaperones.These adaptations disinhibit F1-ATPase activity,remodel mitochondrial proteome,and optimize ATP supply to mitochondria to convergently maintain ??m,ISC biosynthesis,and cell proliferation.We used Myh6-cre,TfamlaxP/loxP mice to deplete mtDNA in mouse heart.mtDNA depletion upregulates glycolysis,downregulates OXPHOS subunits,and post-transcriptionally upregulates mitochondrial biogenesis.ATPIF1,the homolog of Inh1,is post-transcriptionally downregulated.Deleting ATPIF1 in mtDNA-depleted HeLa cell increases ??m and maintains proliferation.But deleting ATP IF 1 in Myh6-cre,TfamloxP/loxP mice cannot extend lifespan.Our study demonstrates OXPHOS deficiency activates adaptive responses to maintain ??m,promoting mitochondria recovery.Because the key effectors we found including Inh1,Mia40,Snfl are conserved evolutionarily,our findings may have broad implications for pathological conditions associated with OXPHOS impairment.