Department of Physiology, Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA.
Center for Biotechnology and Genomic Medicine, Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA.
Nat Commun. 2023 Oct 23;14(1):6721. doi: 10.1038/s41467-023-42564-0.
Mitochondria are critical for metabolic homeostasis of the liver, and their dysfunction is a major cause of liver diseases. Optic atrophy 1 (OPA1) is a mitochondrial fusion protein with a role in cristae shaping. Disruption of OPA1 causes mitochondrial dysfunction. However, the role of OPA1 in liver function is poorly understood. In this study, we delete OPA1 in the fully developed liver of male mice. Unexpectedly, OPA1 liver knockout (LKO) mice are healthy with unaffected mitochondrial respiration, despite disrupted cristae morphology. OPA1 LKO induces a stress response that establishes a new homeostatic state for sustained liver function. Our data show that OPA1 is required for proper complex V assembly and that OPA1 LKO protects the liver from drug toxicity. Mechanistically, OPA1 LKO decreases toxic drug metabolism and confers resistance to the mitochondrial permeability transition. This study demonstrates that OPA1 is dispensable in the liver, and that the mitohormesis induced by OPA1 LKO prevents liver injury and contributes to liver resiliency.
线粒体对于肝脏的代谢稳态至关重要，其功能障碍是肝脏疾病的主要原因。视神经萎缩 1（OPA1）是一种线粒体融合蛋白，在嵴的形成中起作用。OPA1 的破坏会导致线粒体功能障碍。然而，OPA1 在肝功能中的作用知之甚少。在这项研究中，我们在雄性小鼠完全发育的肝脏中删除了 OPA1。出乎意料的是，尽管嵴形态受到破坏，但 OPA1 肝敲除（LKO）小鼠仍然健康，线粒体呼吸不受影响。OPA1 LKO 诱导应激反应，为持续的肝功能建立新的稳态。我们的数据表明，OPA1 是复合物 V 正确组装所必需的，并且 OPA1 LKO 可以保护肝脏免受药物毒性的影响。从机制上讲，OPA1 LKO 会降低有毒药物的代谢，并对线粒体通透性转变产生抗性。这项研究表明，OPA1 在肝脏中是可有可无的，而 OPA1 LKO 诱导的mitohormesis 可以防止肝损伤并有助于肝脏的恢复力。
