MYO6-dependent actin cages encapsulate Parkin-positive damaged mitochondria Antonina J. Kruppa1, Chieko Kishi-Itakura1, Thomas A. Masters1, Joanna E. Rorbach2, Guinevere L. Grice1, John Kendrick-Jones3, James A. Nathan1, Michal Minczuk2, Folma Buss1 1Cambridge Institute for Medical Research, University of Cambridge, UK; 2MRC Mitochondrial Biology Unit, University of Cambridge, UK; 3MRC Laboratory of Molecular Biology, Cambridge, UK
Mitochondrial homeostasis involves the constant remodeling of the mitochondrial network including the isolation and subsequent removal of dysfunctional mitochondria via mitophagy. We have previously shown that myosin VI (MYO6), a unique myosin that moves towards the minus end of actin filaments, directly binds to the autophagy receptors (TAX1BP1, NDP52, and OPTN) and is important in non-selective and selective autophagy pathways for the clearance of invading pathogens and protein aggregates. Recently, the Harper lab identified MYO6 and its adaptors - TOM1, TAX1BP1 and NDP52 - as proteins that associate with Parkin in response to mitochondrial damage using a proteomics-based screen. We confirmed by co-immunoprecipitation that MYO6 indeed forms a complex with Parkin, an E3 ligase that ubiquitinates damaged mitochondria during mitophagy, and we show, for the first time, that this myosin is selectively recruited to damaged mitochondria via its ubiquitin-binding domain. On mitochondria, MYO6 initiates the assembly of F-actin cages, which for their formation also require signaling downstream of the Rho GTPase cdc42 and actin nucleators, such as the Arp2/3 complex, formins, and N-WASP. We demonstrate that these actin cages around mitochondria serve the function of encapsulating damaged mitochondria by forming a physical barrier that prevents refusion with neighbouring populations. In addition, MYO6 also plays a role in the final stages of the mitophagy pathway by mediating mitophagosome maturation. Loss of MYO6 results in an accumulation of mitophagosomes and increase in mitochondrial mass. Finally, we observe downstream mitochondrial dysfunction manifesting as reduced respiratory capacity and decreased ability to rely on oxidative phosphorylation for energy production. Our work uncovers a crucial step in mitochondrial quality control: the formation of MYO6-dependent actin cages that ensure isolation of damaged mitochondria from the network.
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