VPS13D bridges the ER to mitochondria and peroxisomes via Miro

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.

Mitochondrial fission, integrity and completion of mitophagy require separable functions of Vps13D in Drosophila neurons

“…Consistent with other control conditions (Control RNAi and Vps13D heterozygous animals), these objects were not observed in drp1 heterozygous animals. Similar to Vps13D RNAi, and Drp1 RNAi conditions, the PolyUb+/mitoGFP-intermediates in drp1 mutants engage with a phagophore, as they stain positive for Atg8A/B (Fig 4F) 74.4% of the time. Overall, these results demonstrate that neurons with either disrupted Vps13D or Drp1 contain mitophagy intermediates that uniquely lack mitochondrial matrix proteins, and are engaged with a phagophore.…”

“…Vps13D's role in mitochondrial fission likely relies on its function in inter-organelle phospholipid transport, since contacts between the endoplasmic reticulum (ER) and mitochondria have been shown to play a direct role in fission [73]. While this manuscript was under review, further details regarding the cellular localization of Vps13D in cultured cells was reported [74]. Guillén-Samander and colleagues demonstrated that Vps13D localizes to ER/mitochondria and ER/peroxisomal contact sites through associations with mitochondrial/peroxisomal protein Miro and the ER protein Vap.…”

Intertwined and Finely Balanced: Endoplasmic Reticulum Morphology, Dynamics, Function, and Diseases

“…Peroxisomes and the ER must exchange lipids as the synthesis of some lipids, for example, ether phospholipids, begins in peroxisomes but is completed in the ER [132,133]. The lipid transfer protein VPS13D has been discovered at both ER-peroxisome and ERmitochondria contacts, where it interacts with Miro [134], and another, VPS13A, has been found at ER-mitochondria contacts [124], and this lipid transport has been shown to be important for peroxisome biogenesis [135]. The machinery involved in creating ER-peroxisome MCSs has recently been discovered [136] and there is some evidence for non-vesicular ER to peroxisome lipid transport [137].…”

The Link between VAPB Loss of Function and Amyotrophic Lateral Sclerosis

“…This structure is not present in higher eukaryotes, but intensive research has uncovered many other tethering complexes, which may have specific roles in the different processes governed by ER-mitochondria contacts (reviews: [11,128]). Of the numerous complexes identified so far, four contain the VAPs linked to different FFAT-containing proteins on the mitochondrial surface, specifically: protein tyrosine phosphatase-interacting protein 51 (PTPIP51) [60], vacuolar protein sorting (VPS) 13A/ D [42,59,130], and mitoguardin 2 (MIGA2) [65,66] (see Table 1).…”

“…Studies aimed at defining the full complement of VAP interactors have revealed that significant deviations from the initially defined consensus are tolerated [21,[37][38][39]. The complexity of the VAP interactome (VAPome) is further increased by the discovery that some motifs that deviate from the initially defined consensus are regulated by phosphorylation (phospho-FFAT motifs [40][41][42]). The uniquely large number of interactions of the VAP proteins underlies the very many functions that they carry out, as summarised in Table 1.…”