OXPHOS deficiency activates global adaptations to maintain mitochondrial membrane potential

Reduction of mitochondrial membrane potential is a hallmark of mitochondrial dysfunction. It activates adaptive responses in organisms from yeast to human to rewire metabolism, remove depolarized mitochondria, and degrade unimported precursor proteins. It remains unclear how cells maintain mitochondrial membrane potential, which is critical for maintaining iron-sulfur cluster (ISC) synthesis, an indispensable function of mitochondria. Here we show that yeast oxidative phosphorylation mutants deficient in complex III, IV, V, and mtDNA respectively, have graded reduction of mitochondrial membrane potential and proliferation rates. Extensive omics analyses of these mutants show that accompanying mitochondrial membrane potential 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 mitochondrial ATP hydrolysis, remodel mitochondrial proteome, and optimize ATP supply to mitochondria to convergently maintain mitochondrial membrane potential, ISC biosynthesis, and cell proliferation.