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

Nat Commun. 2021 Feb 23;12(1):1252. doi: 10.1038/s41467-021-21525-5.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Amino Acid Sequence
  • Animals
  • COS Cells
  • Chlorocebus aethiops
  • DNA-Binding Proteins / metabolism*
  • Endosomal Sorting Complexes Required for Transport / metabolism*
  • Fatty Acids / metabolism*
  • Fluorescence
  • HEK293 Cells
  • Humans
  • Lipid Droplets / metabolism*
  • Mitochondria / metabolism*
  • Models, Biological
  • Mutant Proteins / metabolism
  • Protein Domains
  • Protein Structure, Secondary
  • Proteins / chemistry
  • Proteins / metabolism*
  • Transcription Factors / metabolism*

Substances

  • DNA-Binding Proteins
  • Endosomal Sorting Complexes Required for Transport
  • Fatty Acids
  • Mutant Proteins
  • Proteins
  • Transcription Factors
  • Tsg101 protein
  • VPS13D protein, human