Miro proteins prime mitochondria for Parkin translocation and mitophagy

Abstract

The Parkinson's disease‐associated protein kinase PINK1 and ubiquitin ligase Parkin coordinate the ubiquitination of mitochondrial proteins, which marks mitochondria for degradation. Miro1, an atypical GTPase involved in mitochondrial trafficking, is one of the substrates tagged by Parkin after mitochondrial damage. Here, we demonstrate that a small pool of Parkin interacts with Miro1 before mitochondrial damage occurs. This interaction does not require PINK1, does not involve ubiquitination of Miro1 and also does not disturb Miro1 function. However, following mitochondrial damage and PINK1 accumulation, this initial pool of Parkin becomes activated, leading to the ubiquitination and degradation of Miro1. Knockdown of Miro proteins reduces Parkin translocation to mitochondria and suppresses mitophagic removal of mitochondria. Moreover, we demonstrate that Miro1 EF‐hand domains control Miro1's ubiquitination and Parkin recruitment to damaged mitochondria, and they protect neurons from glutamate‐induced mitophagy. Together, our results suggest that Miro1 functions as a calcium‐sensitive docking site for Parkin on mitochondria.

PINK1/Parkin Mediated Mitophagy, Ca2+ Signalling, and ER–Mitochondria Contacts in Parkinson’s Disease

“…Their degradation leads to the blockage of mitochondrial movement, promoting the segregation of dysfunctional mitochondria [69]. In addition, a recent paper by Safiulina et al [70] suggested a role for Miro1 in Parkin recruitment to damaged mitochondria. In fact, in rat primary cortical neurons, Miro1 seems to be able to interact with Parkin also in the absence of PINK1 accumulation at the OMM and in basal conditions, suggesting a role for Miro1 as a mitochondrial docking site for the recruitment of Parkin from the cytosol.…”

Miro: A molecular switch at the center of mitochondrial regulation

“…Subsequent work identified Miro as a target of both PINK1 phosphorylation and Parkin ubiquitination in order to degrade damaged mitochondria . Moreover, recent studies suggest that Parkin directly associates with Miro prior to activation by PINK1, suggesting that Miro has direct physical connections to both Parkin and PINK1. These initial results suggested that dissociating mitochondria from the microtubule network is a requirement for the successful turnover of mitophagy.…”

MitophAging: Mitophagy in Aging and Disease

“…However, conditional doubleknockout of Mfn1 and Mfn2 in mice leads to mitochondrial dysfunction and, in line with this, Mfn2-depleted cardiomyocytes are deficient in Parkin recruitment to the mitochondrial outer membrane (Chen et al, 2011;Chen and Dorn, 2013). A similar priming function of mitochondria has been described for other mitochondrial proteins such as Miro1 and VDAC1 (Geisler et al, 2010;Wang et al, 2011;Sun et al, 2012;Safiulina et al, 2019). Recently, the apoptotic protein BAK has been identified as a Parkin target, further connecting Parkin-mediated mitophagy to the regulation of cellular apoptosis (Bernardini et al, 2019).…”