Genetically controlled mtDNA deletions prevent ROS damage by arresting oxidative phosphorylation

Elife. 2022 Jul 8:11:e76095. doi: 10.7554/eLife.76095.

Abstract

Deletion of mitochondrial DNA in eukaryotes is currently attributed to rare accidental events associated with mitochondrial replication or repair of double-strand breaks. We report the discovery that yeast cells arrest harmful intramitochondrial superoxide production by shutting down respiration through genetically controlled deletion of mitochondrial oxidative phosphorylation genes. We show that this process critically involves the antioxidant enzyme superoxide dismutase 2 and two-way mitochondrial-nuclear communication through Rtg2 and Rtg3. While mitochondrial DNA homeostasis is rapidly restored after cessation of a short-term superoxide stress, long-term stress causes maladaptive persistence of the deletion process, leading to complete annihilation of the cellular pool of intact mitochondrial genomes and irrevocable loss of respiratory ability. This shows that oxidative stress-induced mitochondrial impairment may be under strict regulatory control. If the results extend to human cells, the results may prove to be of etiological as well as therapeutic importance with regard to age-related mitochondrial impairment and disease.

Keywords: S. cerevisiae; cell biology; genetics; genome editing; genome stability; genomics; mitochondrial DNA; mitochondrial impairment; oxidative stress.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • DNA Damage
  • DNA, Mitochondrial / genetics
  • DNA, Mitochondrial / metabolism
  • Humans
  • Mitochondria / metabolism
  • Oxidative Phosphorylation*
  • Oxidative Stress / genetics
  • Reactive Oxygen Species / metabolism
  • Superoxides* / metabolism

Substances

  • DNA, Mitochondrial
  • Reactive Oxygen Species
  • Superoxides

Grants and funding

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.