Topology-dependent, bifurcated mitochondrial quality control under starvation

Selective elimination of mitochondria by autophagy is a critical strategy for a variety of physiological processes, including development, cell-fate determination and stress response. Although several mechanisms have been identified as responsible for selective degradation of mitochondria, such as the PINK1-PRKN/PARKIN- and receptor-dependent pathways, aspects of the mechanisms and particularly the principles underlying the selection process of mitochondria remain obscure. Here, we addressed a new selection strategy in which the selective elimination of mitochondria is dependent on organellar topology. We found that populations of mitochondria undergo different topological transformations under serum starvation, either swelling or forming donut shapes. Swollen mitochondria are associated with mitochondrial membrane potential dissipation and PRKN recruitment, which promote their selective elimination, while the donut topology maintains mitochondrial membrane potential and helps mitochondria resist autophagy. Mechanistic studies show that donuts resist autophagy even after depolarization through preventing recruitment of autophagosome receptors CALCOCO2/NDP52 and OPTN even after PRKN recruitment. Our results demonstrate topology-dependent, bifurcated mitochondrial recycling under starvation, that is swollen mitochondria undergo removal by autophagy, while donut mitochondria undergo fission and fusion cycles for reintegration. This study reveals a novel morphological selection for control of mitochondrial quality and quantity under starvation.

通过自噬（autophagy）选择性清除线粒体（mitochondria）是诸多生理过程的关键策略，涵盖发育、细胞命运决定与应激反应。尽管已有数种介导线粒体选择性降解的机制被阐明，例如PINK1-PRKN/帕金（PARKIN）通路与受体依赖通路，但该过程的具体机制，尤其是线粒体选择的核心原则仍未明确。本研究探讨了一种全新的选择策略：线粒体的选择性清除依赖于细胞器拓扑结构。我们发现，在血清饥饿条件下，线粒体群体可发生两种不同的拓扑结构转变：要么出现肿胀，要么形成甜甜圈状结构。肿胀的线粒体伴随线粒体膜电位消散与PRKN招募，进而触发其被选择性清除；而呈甜甜圈状拓扑结构的线粒体则维持线粒体膜电位，得以抵抗自噬过程。机制研究显示，即便在去极化状态下，甜甜圈状线粒体仍可通过阻断自噬体受体CALCOCO2/NDP52与OPTN的招募（即使PRKN已完成招募）来抵抗自噬。我们的研究结果证实，饥饿状态下线粒体的循环回收存在拓扑依赖性的分叉路径：肿胀的线粒体通过自噬被清除，而甜甜圈状线粒体则通过裂变与融合循环实现结构再整合。本研究揭示了一种全新的形态学选择机制，用于调控饥饿状态下的线粒体质量与数量平衡。