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.

• Authors: Jingru Wang, Na Fang, Juan Xiong, Yuanjiao Du, Yue Cao, Wei-Ke Ji
• Journal: Nature communications (Nat Commun) Vol. 12 Issue 1 Pg. 1252 (02 23 2021) ISSN: 2041-1723 [Electronic] England
• PMID: 33623047 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

• 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, metabolism)
• Transcription Factors (metabolism)