OXPHOS deficiency activates global adaptation pathways to maintain mitochondrial membrane potential

Reduction of mitochondrial membrane potential (Delta psi(m)) 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 Delta psi(m), 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, exhibit activated stress responses and progressive reduction of Delta psi(m). Extensive omics analyses of these mutants show that 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 Delta psi(m), ISC biosynthesis, and cell proliferation.

Automated summary

The research reveals that yeast mutants deficient in certain oxidative phosphorylation complexes and mtDNA exhibit progressive reduction of mitochondrial membrane potential. These mutants activate adaptive responses, including remodeling of mitochondrial proteome and reshaping of cellular metabolism.