Mitochondrial complex III deficiency drives c-MYC overexpression and illicit cell cycle entry leading to senescence and segmental progeria

• Published in: Nature communications Vol. 14; no. 1; pp. 2356 - 23
• Main Authors: Purhonen, Janne, Banerjee, Rishi, Wanne, Vilma, Sipari, Nina, Mörgelin, Matthias, Fellman, Vineta, Kallijärvi, Jukka
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 24.04.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/51; 14; 14/28; 14/63; 38/1; 38/22; 38/77; 38/88; 38/90; 42/41; 45; 59; 631/443/319/333/1465; 631/443/7; 64; 64/60; 692/4017; 82/29; 96; Aging; Alternative oxidase; Animals; Basic Medicine; c-Myc protein; Cell and Molecular Biology; Cell Cycle; Cell growth; Cell proliferation; Cell- och molekylärbiologi; Cellular Senescence - genetics; Damage; Deoxyribonucleic acid; DNA; DNA damage; Electron Transport Complex III; Genomic instability; Hepatocytes; Humanities and Social Sciences; Kidneys; Lethality; Medical and Health Sciences; Medicin och hälsovetenskap; Medicinska och farmaceutiska grundvetenskaper; Mice; Mitochondria; Mitochondrial Diseases; Mitosis; Modulators; multidisciplinary; Myc protein; Oxidative phosphorylation; Pathogenesis; Phenotypes; Phosphorylation; Progeria; Progeria - pathology; Progeroid syndromes; Science; Science (multidisciplinary); Senescence
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-38027-1

Accumulating evidence suggests mitochondria as key modulators of normal and premature aging, yet whether primary oxidative phosphorylation (OXPHOS) deficiency can cause progeroid disease remains unclear. Here, we show that mice with severe isolated respiratory complex III (CIII) deficiency display nuclear DNA damage, cell cycle arrest, aberrant mitoses, and cellular senescence in the affected organs such as liver and kidney, and a systemic phenotype resembling juvenile-onset progeroid syndromes. Mechanistically, CIII deficiency triggers presymptomatic cancer-like c-MYC upregulation followed by excessive anabolic metabolism and illicit cell proliferation against lack of energy and biosynthetic precursors. Transgenic alternative oxidase dampens mitochondrial integrated stress response and the c-MYC induction, suppresses the illicit proliferation, and prevents juvenile lethality despite that canonical OXPHOS-linked functions remain uncorrected. Inhibition of c-MYC with the dominant-negative Omomyc protein relieves the DNA damage in CIII-deficient hepatocytes in vivo. Our results connect primary OXPHOS deficiency to genomic instability and progeroid pathogenesis and suggest that targeting c-MYC and aberrant cell proliferation may be therapeutic in mitochondrial diseases. Mitochondria modulate both normal and premature aging, yet if primary oxidative phosphorylation deficiency can cause progeria has been unclear. Here, the authors show that mice with severe isolated respiratory complex III deficiency display cellular senescence and juvenile-onset segmental progeria.