Mitochondria are the main site for generating reactive oxygen species, which are key players in diverse biological processes. However, the molecular pathways of redox signal transduction from the matrix to the cytosol are poorly defined. Here we report an inside-out redox signal of mitochondria. Cysteine oxidation of MIC60, an inner mitochondrial membrane protein, triggers the formation of disulfide bonds and the physical association of MIC60 with Miro, an outer mitochondrial membrane protein. The oxidative structural change of this membrane-crossing complex ultimately elicits cellular responses that delay mitophagy, impair cellular respiration and cause oxidative stress. Blocking the MIC60–Miro interaction or reducing either protein, genetically or pharmacologically, extends lifespan and health-span of healthy fruit flies, and benefits multiple models of Parkinson’s disease and Friedreich’s ataxia. Our discovery provides a molecular basis for common treatment strategies against oxidative stress.

线粒体是产生活性氧的主要场所，活性氧是多种生物过程的关键参与者。然而，从基质到细胞质的氧化还原信号转导的分子途径尚不清楚。在这里，我们报告了线粒体由内而外的氧化还原信号。 MIC60（一种线粒体内膜蛋白）的半胱氨酸氧化会触发二硫键的形成以及 MIC60 与 Miro（一种线粒体外膜蛋白）的物理结合。这种跨膜复合物的氧化结构变化最终引发细胞反应，延迟线粒体自噬、损害细胞呼吸并引起氧化应激。从基因或药理学角度阻断 MIC60-Miro 相互作用或减少任一蛋白质，可以延长健康果蝇的寿命和健康寿命，并有利于帕金森病和弗里德赖希共济失调的多种模型。我们的发现为抗氧化应激的常见治疗策略提供了分子基础。