FBS Colloquia No.399Laboratory of Mitochondrial Dynamics

Locking and unlocking mechanisms for initiation of selective mitochondrial clearance

Selective autophagy-dependent degradation of dysfunctional or excess mitochondria, termed mitophagy, is an evolutionarily conserved process that contributes to mitochondrial quality and quantity control. Accumulating evidence suggests that both aberrantly accelerated and suppressed mitophagy may compromise cellular homeostasis, ultimately leading to a myriad of disorders. Thus, cells are likely to utilize fine-tuning mechanisms that properly control clearance of mitochondria. In the budding yeast Saccharomyces cerevisiae, mitophagy occurs in a manner dependent on Atg32, a mitochondrial outer membrane protein that directly interacts with Atg11, a scaffold protein necessary for core Atg protein assembly, thereby forming a mitophagy initiation site to generate autophagosomes surrounding mitochondria. Atg32-Atg11 interactions are regulated by several kinase and phosphatase, serving as a molecular switch for mitophagy initiation. Our recent findings raise the possibility that Atg32 is a self-inhibitory protein preventing Atg11 binding via its intramolecular interactions, and that relief of this self-inhibition leads to oligomerization-mediated phase separation of the mitophagy initiation complex. In this colloquium, the basic principles of mitochondrial clearance and the implications for mitophagy in human health and disease will also be discussed.