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

Jingru Wang, Na Fang, Juan Xiong, Yuanjiao Du, Yue Cao and Wei-Ke Ji ()
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Jingru Wang: Huazhong University of Science and Technology
Na Fang: Huazhong University of Science and Technology
Juan Xiong: Huazhong University of Science and Technology
Yuanjiao Du: Huazhong University of Science and Technology
Yue Cao: Huazhong University of Science and Technology
Wei-Ke Ji: Huazhong University of Science and Technology

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-21525-5

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