VPS13D bridges the ER to Miro containing membranes

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 membrane GTPase Gem1 is an accessory factor of ERMES, an ER-mitochondria tethering complex that contains lipid transport domains and plays a function, partially redundant with VPS13, in lipid transfer between the two organelles. In metazoa, where VPS13, but not ERMES, is present, the Gem1 orthologue Miro has been linked to mitochondrial motility but not to lipid transport. Here we show that Miro recruits to mitochondria the lipid transport protein VPS13D which, like Miro, is an essential protein in mammals, and whose localization had remained elusive. We also show that VPS13D can tether mitochondria to the ER in a Miro- and VAP-dependent way. 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.SummaryProtein-mediated ER-mitochondria lipid transfer is critical for eukaryotic cells. However, the underlying machinery is not well conserved. Guillén-Samander et al, show that Gem1/Miro is an evolutionary conserved link between the yeast ERMES complex and the mammalian lipid transfer protein VPS13D.

Sequence analysis and structural predictions of lipid transfer bridges in the repeating beta groove (RBG) superfamily reveals past and present domain variations affecting form, function and interactions of VPS13, ATG2, SHIP164, Hobbit and Tweek

“…The 12 RBG domains in VPS13A align well with those in yeast Vps13 (yVps13) (Figure 3B) and in most plant homologs (Figure 3C), indicating that this is an ancient form. The increased number of domains in VPS13C and VPS13D fits with previous observations that their extended length originated from internal duplications of ~500 residues (Kumar et al, 2018;Guillen-Samander et al, 2021). The basis for variation in RBG domain number may relate to width of contact size bridged by individual homologs in a way that has yet to be studied.…”

“…Secondly, the majority of central RBG domains arose by internal duplication from two complete domains in an ancestral protein with four domains. Thirdly, previously unknown accessory domains near the C-terminus of VPS13B and plant VPS13 homologs are described, which likely provide interaction sites for partners, alongside those already identified for membrane targeting (Bean et al, 2018;Kumar et al, 2018;Park and Neiman, 2020;Guillen-Samander et al, 2021) and for specific functions such as lipid scramblases (Ghanbarpour et al, 2021;Orii et al, 2021;Adlakha et al, 2022). Fourth, the extreme ends of RBG multimers are shown typically to be adapted to interact with bilayers, however the C-terminus of SHIP164 is an exception better suited to interact with a protein, most likely itself.…”

SHIP164 is a Chorein Motif Containing Lipid Transport Protein that Controls Membrane Dynamics and Traffic at the Endosome-Golgi Interface

“…Moreover, until now we have not identified the binding of SHIP164 to any ER protein. SHIP164 does not have an FFAT or FFAT-like motif that, as in the case of VPS13 6,60 , could account for binding to the ER protein VAP 61,62 . In spite of these considerations, binding of SHIP164 to the ER cannot be excluded.…”

Vmp1, Vps13D, and Marf/Mfn2 function in a conserved pathway to regulate mitochondria and ER contact in development and disease

“…For example, overexpression of a peroxisome-localizing variant of Miro increased recruitment of Vps13D to peroxisomes in COS7 cells. 37 These findings suggest that, in addition to mitophagy, there are still uncharacterized and context-dependent functions of Vps13D.…”