Oxphos Deficiency Activates Global Adaptations To Maintain Mitochondrial Membrane Potential

Oxidative phosphorylation(OXPHOS)generates mitochondrial membrane potential(△ψm)to synthesize ATP and drive protein import and metabolite transportation.Reduction of △ψm caused by OXPHOS dysfunction is a life-threatening condition because △ψm maintains the synthesis of iron-sulfur cluster(ISC),an indispensable cofactor for many house-keeping enzymes.Decreased △ψm 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 △ψm.Here we have analyzed the adaptive changes of transcriptome and mitochondrial proteome in yeast and mouse models to understand whether and how cells maintain △ψm under OXPHOS deficiency.Yeast oxidative phosphorylation mutants deficient in complex Ⅲ,Ⅳ,Ⅴ,and mtDNA respectively,have graded reduction of △ψm and proliferation rates.Extensive Omics analyses of these mutants show that accompanying △ψm 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 △ψm,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 △ψm 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 △ψm,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.