VPS13D bridges the ER to mitochondria and peroxisomes via Miro.

Andrés Guillén-Samander,Hongying Shen,Michael G Hanna,Ni Tang,Marianna Leonzino,Pietro De Camilli

doi:10.1083/jcb.202010004

Andrés Guillén-Samander, Hongying Shen + Show 4 more

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https://doi.org/10.1083/jcb.202010004

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Abstract

Mitochondria, which are excluded from the secretory pathway, depend on lipid transport proteins for their lipid supply from the ER, where most lipids are synthesized. In yeast, the outer mitochondrial membrane GTPase Gem1 is an accessory factor of ERMES, an ER-mitochondria tethering complex that contains lipid transport domains and that functions, partially redundantly with Vps13, in lipid transfer between the two organelles. In metazoa, where VPS13, but not ERMES, is present, the Gem1 orthologue Miro was linked to mitochondrial dynamics but not to lipid transport. Here we show that Miro, including its peroxisome-enriched splice variant, recruits the lipid transport protein VPS13D, which in turn binds the ER in a VAP-dependent way and thus could provide a lipid conduit between the ER and mitochondria. These findings reveal a so far missing link between function(s) of Gem1/Miro in yeast and higher eukaryotes, where Miro is a Parkin substrate, with potential implications for Parkinson's disease pathogenesis.

Highlights

Homeostasis of membranous subcellular organelles relies on appropriate synthesis, metabolism, and distribution of bilayer lipids
Our findings provide insight into the properties of VPS13D, a VPS13 family member previously shown to have an impact on mitochondrial biology based on loss-of-function studies, but whose site of action remained elusive
We show that VPS13D can bridge mitochondria to the ER and identify proteins on the two organelles responsible for this localization: the protein vesicle-associated membrane protein (VAP) in the ER membrane and the protein Miro in the outer mitochondrial membrane (OMM) (Fig. 6 C)

Summary

Introduction

Homeostasis of membranous subcellular organelles relies on appropriate synthesis, metabolism, and distribution of bilayer lipids. ER–mitochondria encounter structure (ERMES), a heterotetrametric protein complex that contains lipid transport modules and tethers the ER to the outer mitochondrial membrane (OMM), was shown to account for some of this transport (Kornmann et al, 2009). Another yeast protein, Vps, which localizes at membrane contact sites, albeit not ER–mitochondria contacts in this organism, was shown to have partially overlapping function with ERMES, possibly by participating in an alternative route for the delivery of lipids from the ER to mitochondria via the vacuole (Lang et al, 2015; Park et al, 2016; John Peter et al, 2017). Splice variants of Miro (Miro1v2 and Miro1v4) were shown to be enriched at peroxisomes and to be implicated in the dynamics of these organelles as well (Okumoto et al, 2018; Castro et al, 2018; Covill-Cooke et al, 2020)

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