There is a tight association between mitochondrial dysfunction and neurodegenerative diseases and axons that are particularly vulnerable to degeneration, but how mitochondria are maintained in axons to support their physiology remains poorly defined. In an in vivo forward genetic screen for mutants altering axonal mitochondria, we identified tsg101. Neurons mutant for tsg101 exhibited an increase in mitochondrial number and decrease in mitochondrial size. TSG101 is best known as a component of the endosomal sorting complexes required for transport (ESCRT) complexes; however, loss of most other ESCRT components did not affect mitochondrial numbers or size, suggesting TSG101 regulates mitochondrial biology in a noncanonical, ESCRT-independent manner. The TSG101-mutant phenotype was not caused by lack of mitophagy, and we found that autophagy blockade was detrimental only to the mitochondria in the cell bodies, arguing mitophagy and autophagy are dispensable for the regulation of mitochondria number in axons. Interestingly, TSG101 mitochondrial phenotypes were instead caused by activation of PGC-1ɑ/Nrf2-dependent mitochondrial biogenesis, which was mTOR independent and TFEB dependent and required the mitochondrial fission–fusion machinery. Our work identifies a role for TSG101 in inhibiting mitochondrial biogenesis, which is essential for the maintenance of mitochondrial numbers and sizes, in the axonal compartment.

线粒体功能障碍与神经退行性疾病和特别容易退化的轴突之间存在紧密联系，但线粒体如何在轴突中维持以支持其生理机能仍不清楚。在针对改变轴突线粒体的突变体的体内正向遗传筛选中，我们确定了 tsg101。tsg101的神经元突变体表现出线粒体数量的增加和线粒体大小的减少。TSG101 最为人熟知的是运输所需的内体分选复合物 (ESCRT) 复合物的一个组成部分；然而，大多数其他 ESCRT 成分的丢失并不影响线粒体的数量或大小，这表明 TSG101 以非规范的、ESCRT 独立的方式调节线粒体生物学。TSG101 突变表型不是由缺乏线粒体自噬引起的，我们发现自噬阻断仅对细胞体中的线粒体有害，认为线粒体自噬和自噬对于轴突中线粒体数量的调节是可有可无的。有趣的是，TSG101 线粒体表型是由 PGC-1ɑ/Nrf2 依赖性线粒体生物发生的激活引起的，这是 mTOR 独立的和 TFEB 依赖的，需要线粒体裂变-融合机制。我们的工作确定了 TSG101 在抑制线粒体生物合成中的作用，这对于维持轴突区室中的线粒体数量和大小至关重要。