VPS13D bridges the ER to mitochondria and peroxisomes via Miro

• DOI: 10.1083/jcb.202010004
• Publication Date: 2021-04-23T13:22:27Z
• Authors: Andrés Guillén-Sa...; Marianna Leonzino; Michael G. Hanna; Ni Tang; Hongying Shen; Pietro De Camilli
• Keywords: Ubiquitin-Protein Ligases; Eukaryota; Proteins; Biological Transport; Parkinson Disease; Endoplasmic Reticulum; Mitochondrial Dynamics; Article; Cell Line; GTP Phosphohydrolases; Mitochondria; neurodegenerative disease; Miro; Cell Line, Tumor; COS Cells; Chlorocebus aethiops; VPS13D; Peroxisomes; Animals; Humans; Ataxia; lipid transfer; HeLa Cells

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.