Topology-dependent, bifurcated mitochondrial quality control under starvation

Abstract

ABSTRACT 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.