Purhonen 2023 Nat Commun
| Purhonen J, Banerjee R, Wanne V, Sipari N, Mörgelin M, Fellman V, Kallijärvi J (2023) Mitochondrial complex III deficiency drives c-MYC overexpression and illicit cell cycle entry leading to senescence and segmental progeria. Nat Commun 14:2356. https://doi.org/10.1038/s41467-023-38027-1 |
Purhonen Janne, Banerjee Rishi, Wanne Vilma, Sipari Nina, Moergelin Matthias, Fellman Vineta, Kallijaervi Jukka (2023) Nat Commun
Abstract: 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.
• Bioblast editor: Plangger M • O2k-Network Lab: FI Helsinki Mervaala E, FI Helsinki Wartiovaara A
Labels: MiParea: Respiration
Pathology: Aging;senescence
Organism: Mouse Tissue;cell: Liver, Kidney Preparation: Isolated mitochondria Enzyme: Complex III
Coupling state: LEAK, OXPHOS Pathway: N, NS HRR: Oxygraph-2k
2024-07
