Genetically controlled mtDNA deletions prevent ROS damage by arresting oxidative phosphorylation

• Published in: eLife Vol. 11
• Main Authors: Stenberg, Simon, Li, Jing, Gjuvsland, Arne B, Persson, Karl, Demitz-Helin, Erik, González Peña, Carles, Yue, Jia-Xing, Gilchrist, Ciaran, Ärengård, Timmy, Ghiaci, Payam, Larsson-Berglund, Lisa, Zackrisson, Martin, Smits, Silvana, Hallin, Johan, Höög, Johanna L, Molin, Mikael, Liti, Gianni, Omholt, Stig W, Warringer, Jonas
• Format: Journal Article
• Language: English
• Published: England eLife Science Publications, Ltd 08.07.2022; eLife Sciences Publications, Ltd; eLife Sciences Publications Ltd
• Subjects: Cell Biology; Cellbiologi; Cells; DNA; DNA Damage; DNA, Mitochondrial - genetics; DNA, Mitochondrial - metabolism; Enzymes; Evolutionary Biology; Evolutionsbiologi; Genes; Genetics; Genetics and Genomics; Genetik; genome editing; genome stability; Humans; metabolism; Mitochondria; Mitochondria - metabolism; Mitochondrial; Mitochondrial DNA; mitochondrial impairment; mtDNA; Oxidative Phosphorylation; Oxidative Stress; Oxidative Stress - genetics; Reactive Oxygen Species; Reactive Oxygen Species - metabolism; Superoxide; Superoxides; Superoxides - metabolism; genome editing; genome stability; cell biology; genetics; mitochondrial DNA; mitochondrial impairment; genomics; oxidative stress; S. cerevisiae
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.76095

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.