Myosin VI-Dependent Actin Cages Encapsulate Parkin-Positive Damaged Mitochondria

Summary

Mitochondrial quality control is essential to maintain cellular homeostasis and is achieved by removing damaged, ubiquitinated mitochondria via Parkin-mediated mitophagy. Here, we demonstrate that MYO6 (myosin VI), a unique myosin that moves toward the minus end of actin filaments, forms a complex with Parkin and is selectively recruited to damaged mitochondria via its ubiquitin-binding domain. This myosin motor initiates the assembly of F-actin cages to encapsulate damaged mitochondria by forming a physical barrier that prevents refusion with neighboring populations. Loss of MYO6 results in an accumulation of mitophagosomes and an increase in mitochondrial mass. In addition, 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.

Graphical Abstract

Highlights

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  MYO6 forms a complex with Parkin and is recruited to damaged mitochondria

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  MYO6 triggers F-actin cage assembly around dysfunctional mitochondria

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  Actin cages form a barrier thereby preventing refusion of damaged mitochondria

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  Loss of MYO6 causes an accumulation of mitophagosomes and mitochondrial dysfunction

Abstract

Kruppa et al. demonstrate that MYO6 forms a complex with Parkin and is recruited to damaged, ubiquitinated mitochondria. MYO6 promotes F-actin cage assembly to isolate and prevent refusion of dysfunctional organelles. Loss of MYO6 leads to a mitophagy defect with an accumulation of mitophagosomes and downstream mitochondrial dysfunction.