Abstract
SummaryMitochondrial 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.
Highlights
Mitochondrial homeostasis involves the constant remodeling of the mitochondrial network through fission and fusion events, and requires the isolation and subsequent removal of dysfunctional mitochondria from this dynamic network
MYO6 Is Recruited to Damaged Mitochondria and Interacts with Parkin First, we investigated whether MYO6 plays a role in the clearance of damaged mitochondria by Parkin-mediated mitophagy
Using superresolution structured illumination microscopy (SR-SIM), we observed that endogenous MYO6, which normally resides on intracellular vesicles, the plasma membrane, and in the cytosol (Buss et al, 1998; Chibalina et al, 2007; Tumbarello et al, 2012; Warner et al, 2003), was strongly recruited to and colocalized with Parkinpositive damaged mitochondria stained for cytochrome c after 2 h of carbonyl cyanide 3-chlorophenylhydrazone (CCCP) treatment in 90% of HEK293 cells expressing Parkin (Figures 1A–1C) or after 3 h treatment with oligomycin/antimycin A (OA) (Figure S1A)
Summary
Mitochondrial homeostasis involves the constant remodeling of the mitochondrial network through fission and fusion events, and requires the isolation and subsequent removal of dysfunctional mitochondria from this dynamic network. Damaged organelles are targeted for clearance via a specialized selective autophagy pathway termed mitophagy (Narendra et al, 2008). A hallmark of mitochondrial damage is the loss of membrane potential resulting in recruitment of Parkin to the outer mitochondrial membrane (OMM), which extensively ubiquitinates OMM proteins thereby amplifying the mitophagy signal (Nguyen et al, 2016). Cargospecific autophagy receptors (OPTN, NDP52, and TAX1BP1) recognize and capture ubiquitinated mitochondria via their ubiquitin-binding domains and simultaneously bind to LC3 on autophagosomal membranes via their LC3 interacting region motif (Lazarou et al, 2015; Moore and Holzbaur, 2016; Rogov et al, 2014; Wong and Holzbaur, 2014). The dysfunctional, ubiquitinated mitochondria are sequestered into double-membraned structures called autophagosomes, forming mitophagosomes, which fuse with lysosomes for degradation (Ktistakis and Tooze, 2016)
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