GSE162197
OXPHOS deficiency activates global adaptation pathways 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. Overall design: 1. Differential expression analysis between OXPHOS mutants and WT cells. 2. Examination of gene expression upon PUF3 deletion in WT, atp7D and r0 cells. 3. Examination of gene expression upon blocking Puf3 hyperphosphorylation in WT and r0 cells. 4. Examination of gene expression upon SNF1 deletion in WT and r0 cells. 5. Examination of gene expression upon INH1 overexpression in r0 cells. 6. Examination of gene expression upon MIG1 deletion in snf1 r0 cells. 7. Analysis of ribosome footprints in WT, puf3D, r0, puf3D r0 cells. Three biological replicates were prepared for mRNA profiles, and two biological replicates were prepared for ribosome profiling.