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

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.
Mesh Terms:
Amino Acid Motifs, Amino Acid Sequence, Animals, COS Cells, Chlorocebus aethiops, DNA-Binding Proteins, Endosomal Sorting Complexes Required for Transport, Fatty Acids, Fluorescence, HEK293 Cells, Humans, Lipid Droplets, Mitochondria, Models, Biological, Mutant Proteins, Protein Domains, Protein Structure, Secondary, Proteins, Transcription Factors
Nat Commun
Date: Dec. 23, 2020
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