积累的证据表明线粒体是正常老化和过早衰老的关键调节因子，然而原发性氧化磷酸化缺陷是否可以导致早衰性疾病仍不清楚。在这里，我们展示了严重的独立呼吸链复合物III（CIII）缺陷小鼠在受影响的器官如肝脏和肾脏中显示出核DNA损伤、细胞周期阻滞、异常有丝分裂和细胞衰老，以及类似于儿童肉芽肿早老综合征的全身性表型。在机械方面，CIII缺陷触发了早期癌症样的c-MYC上调，随后是过度的同化代谢和违法的细胞增殖，这些都会导致能量和生物合成前体缺乏。转基因替代氧化酶减轻了线粒体整合应激反应和c-MYC的诱导，抑制了违法增殖，并防止了儿童致死，尽管经典的OXPHOS相关功能仍未得到纠正。以显性负效的Omomyc蛋白抑制c-MYC可以缓解CIII缺陷肝细胞中的DNA损伤。我们的研究结果将原发性OXPHOS缺陷与基因组不稳定性和早衰性病理机制联系起来，并提示针对c-MYC和异常细胞增殖可能是线粒体疾病的治疗方法。©2023年，作者。

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.© 2023. The Author(s).