The heat shock proteins, Hsp82 and Hsc82, differentially regulate mitochondrial integrity and metabolism in Saccharomyces cerevisiae

Heat shock proteins (Hsps) are highly conserved across species and exhibit evolutionarily conserved cellular functions. The Hsp90 family is implicated in various cellular adaptations in higher eukaryotes. Among them, the mitochondrial homologue TRAP1 (Tumor necrosis factor receptor-associated protein-1) promotes metabolic rewiring in cancer cells. The budding yeast Saccharomyces cerevisiae contains two Hsp90 isoforms, Hsc82 and Hsp82. To examine the mitochondrial functions of these isoforms, we developed hsc82Δ and hsp82Δ systems and studied their influence on mitochondrial integrity and cellular metabolism. We report that hsc82Δ but not hsp82Δ affects mitochondrial integrity and metabolism. A decrease in mitochondrial oxidative phosphorylation (OXPHOS) in hsc82Δ cells resulted in metabolic rewiring through enhanced aerobic glycolysis, indicating that Hsc82 regulates OXPHOS. The altered mitochondrial morphology and membrane potential in hsc82Δ cells, but not in hsp82Δ , correlated with metabolic switching, suggesting that Hsc82 is critical for the maintenance of mitochondrial integrity and function. Proteome analyses confirmed impaired OXPHOS and ATP synthesis in hsc82Δ cells. The NMR studies furthered our understanding that Hsc82 modulates metabolic switching in the presence of glucose. Our findings expose involvement of Hsc82 in regulating mitochondrial integrity and cellular energy metabolism.