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

Abstract

Accumulating evidence suggests mitochondria as key modulators of normal and premature aging, yet whether primary deficiency of oxidative phosphorylation (OXPHOS) 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, cellular senescence, and laminopathy-like nuclei in the affected organs such as liver and kidney, and a systemic phenotype strikingly resembling juvenile-onset laminopathic and DNA repair-deficient progeroid syndromes. Mechanistically, CIII deficiency triggered presymptomatic cancer-like c-MYC upregulation followed by excessive anabolic metabolism and illicit cell proliferation against lack of energy and biosynthetic precursors. CIII-independent coenzyme Q oxidation dampened mitochondrial integrated stress response and the c-MYC induction, suppressed the illicit proliferation, and prevented juvenile lethality despite that canonical OXPHOS-linked functions remained uncorrected. Inhibition of c-MYC by expression of a dominant-negative Omomyc protein relieved the DNA damage in CIII-deficient hepatocytes in vivo. Our results unequivocally connect primary OXPHOS deficiency to genomic instability and progeroid disease and suggest that targeting c-MYC and aberrant cell proliferation may provide novel therapeutic strategies in mitochondrial diseases.