An ESCRT-dependent step in fatty acid transfer from lipid droplets to mitochondria through VPS13D−TSG101 interactions

Abstract

Upon starvation, cells rewire their metabolism, switching from glucose-based metabolism to mitochondrial oxidation of fatty acids, which require the transfer of FAs from lipid droplets (LDs) to mitochondria at mitochondria−LD membrane contact sites (MCSs). However, factors responsible for FA transfer at these MCSs remain uncharacterized. Here, we demonstrate that vacuolar protein sorting-associated protein 13D (VPS13D), loss-of-function mutations of which cause spastic ataxia, coordinates FA trafficking in conjunction with the endosomal sorting complex required for transport (ESCRT) protein tumor susceptibility 101 (TSG101). The VPS13 adaptor-binding domain of VPS13D and TSG101 directly remodels LD membranes in a cooperative manner. The lipid transfer domain of human VPS13D binds glycerophospholipids and FAs in vitro. Depletion of VPS13D, TSG101, or ESCRT-III proteins inhibits FA trafficking from LDs to mitochondria. Our findings suggest that VPS13D mediates the ESCRT-dependent remodeling of LD membranes to facilitate FA transfer at mitochondria-LD contacts.

VPS13D interacts with VCP/p97 and negatively regulates ER- mitochondrial interactions

“…Mutations in VPS13D were recently identified in human neurodegenerative diseases (a new type of autosomal recessive spastic ataxia), and mitochondria in these patients showed severe defects in both morphology and function (Gauthier et al, 2018;Seong et al, 2018). Recent studies showed that VPS13D was localized to various organelle MCSs under diverse metabolic conditions, including the ER-mitochondrial/peroxisomal MCSs under normal conditions and mitochondria-lipid droplet junctions under starvation (Baldwin et al, 2021;Guillen-Samander et al, 2021;Wang et al, 2021). Here, we demonstrated a critical role of VPS13D in the negative regulation of ER-mitochondrial MCSs.…”

“…Therefore, multiple pathways may be responsible for the ER-mitochondrial hyper-tethering in VPS13D suppressed cells. Since previous studies showed that VPS13 proteins including VPS13D bind and transfer glycerophospholipids and lipid fatty acids moieties in vitro, VPS13D is a potential lipid transfer protein (Kumar et al, 2018;Wang et al, 2021). One possibility is that the lipid transfer activities of VPS13D may be involved in the regulation of the ER-mitochondrial interactions.…”

Perspectives on Mitochondria–ER and Mitochondria–Lipid Droplet Contact in Hepatocytes and Hepatic Lipid Metabolism

“…VPS13D and TSG101 coordinately regulate the trafficking of the free fatty acid (FFA) between mitochondria and LDs at contact sites in cultured cells. The depletion of VPS13D or TSG101 inhibits FFA trafficking from LDs to the mitochondria based on a BODIPY-conjugated FFA assay [ 64 ]. These recent findings demonstrate the critical roles of VPS13 family proteins in regulating organelle contact, dynamics and biogenesis, as well as autophagy and lipid metabolism, which are vital for cellular function and homeostasis.…”

Lipid Droplet-Organelle Contact Sites as Hubs for Fatty Acid Metabolism, Trafficking, and Metabolic Channeling

“…More recently, a new ESCRT-dependent mechanism by which FAs are trafficked from LDs to mitochondria was described. This was shown to be mediated by the lipid transfer protein VPS13D and the ESCRT protein Tsg101 ( Wang et al, 2021 ). Finally, the observation of LD-mitochondria contact sites in yeast, where β-oxidation takes place solely in peroxisomes ( Pu et al, 2011 ), as well the notion that several lipid metabolic enzymes can localize to both mitochondria and LDs in yeast), indicate that LD-mitochondria contacts likely have lipid metabolic functions beyond channeling of FA for β-oxidation.…”