Mitochondrial dysfunction and mitophagy are often hallmarks of neurodegenerative diseases such as autosomal dominant optic atrophy (ADOA) caused by mutations in the key mitochondrial dynamics protein optic atrophy 1 (Opa1). However, the second messengers linking mitochondrial dysfunction to initiation of mitophagy remain poorly characterized. Here, we show in mammalian and nematode neurons that Opa1 mutations trigger Ca²⁺-dependent mitophagy. Deletion or expression of mutated Opa1 in mouse retinal ganglion cells and Caenorhabditis elegans motor neurons lead to mitochondrial dysfunction, increased cytosolic Ca²⁺ levels, and decreased axonal mitochondrial density. Chelation of Ca²⁺ restores mitochondrial density in neuronal processes, neuronal function, and viability. Mechanistically, sustained Ca²⁺ levels activate calcineurin and AMPK, placed in the same genetic pathway regulating axonal mitochondrial density. Our data reveal that mitophagy in ADOA depends on Ca²⁺-calcineurin-AMPK signaling cascade.

线粒体功能障碍和线粒体自噬通常是神经退行性疾病的标志，例如由关键线粒体动力学蛋白视神经萎缩 1 (Opa1) 突变引起的常染色体显性遗传性视神经萎缩 (ADOA)。然而，将线粒体功能障碍与线粒体自噬启动联系起来的第二信使仍然缺乏特征。在这里，我们在哺乳动物和线虫神经元中显示 Opa1 突变触发 Ca ²⁺依赖性线粒体自噬。小鼠视网膜神经节细胞和秀丽隐杆线虫运动神经元中突变 Opa1 的缺失或表达导致线粒体功能障碍、细胞溶质 Ca ²⁺水平升高和轴突线粒体密度降低。Ca ^2+螯合恢复神经元过程中的线粒体密度、神经元功能和活力。从机制上讲，持续的 Ca ²⁺水平激活钙调神经磷酸酶和 AMPK，它们位于调节轴突线粒体密度的相同遗传途径中。我们的数据表明，ADOA 中的线粒体自噬依赖于 Ca ²⁺ -calcineurin-AMPK 信号级联。