Control of Mitochondrial Superoxide Production Includes Programmed mtDNA Deletion and Restoration

Age-related diseases are intimately linked to mitochondrial impairment. Whether oxidative stress is a major driver of this impairment is still a contentious issue. Here we show that yeast cells adapt to intramitochondrial superoxide anion ( ) production beyond antioxidant defenses by swiftly reducing the copy numbers of mitochondrial electron transport chain (ETC) genes, while maintaining the copy numbers of undeleted mtDNA. The copy numbers of the ETC genes are rapidly restored after cessation of a short-term stress, whereas long-term stress causes irreversible loss of this capacity through maladaptive persistence of the mtDNA deletion process. As chronic oxidative stress is a hallmark of ageing, maladaptive mtDNA deletion may be a marked contributor to age-related mtDNA impairment.