Max Planck Institute for Biology of Ageing, Cologne, Germany.
Institute of Experimental Genetics, German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany.
Sci Adv. 2024 Aug 2;10(31):eadp0443. doi: 10.1126/sciadv.adp0443.
Mitochondrial fusion and fission accompany adaptive responses to stress and altered metabolic demands. Inner membrane fusion and cristae morphogenesis depends on optic atrophy 1 (Opa1), which is expressed in different isoforms and is cleaved from a membrane-bound, long to a soluble, short form. Here, we have analyzed the physiological role of Opa1 isoforms and Opa1 processing by generating mouse lines expressing only one cleavable Opa1 isoform or a non-cleavable variant thereof. Our results show that expression of a single cleavable or non-cleavable Opa1 isoform preserves embryonic development and the health of adult mice. Opa1 processing is dispensable under metabolic and thermal stress but prolongs life span and protects against mitochondrial cardiomyopathy in OXPHOS-deficient mice. Mechanistically, loss of Opa1 processing disturbs the balance between mitochondrial biogenesis and mitophagy, suppressing cardiac hypertrophic growth in hearts. Our results highlight the critical regulatory role of Opa1 processing, mitochondrial dynamics, and metabolism for cardiac hypertrophy.
线粒体融合和裂变伴随着对压力和代谢需求变化的适应性反应。内膜融合和嵴形态发生依赖于视神经萎缩 1（Opa1），它以不同的同工型表达，并从膜结合的长形式切割为可溶性的短形式。在这里，我们通过生成仅表达一种可切割的 Opa1 同工型或其不可切割变体的小鼠系来分析 Opa1 同工型和 Opa1 加工的生理作用。我们的结果表明，表达单一可切割或不可切割的 Opa1 同工型可保留胚胎发育和成年小鼠的健康。Opa1 加工在代谢和热应激下是可有可无的，但可延长寿命并预防 OXPHOS 缺陷型小鼠的线粒体心肌病。从机制上讲，失去 Opa1 加工会扰乱线粒体生物发生和线粒体自噬之间的平衡，抑制心脏的肥大生长。我们的结果强调了 Opa1 加工、线粒体动力学和代谢对心脏肥大的关键调节作用。
