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

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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)

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.

Suggested Citation

  • Jingru Wang & Na Fang & Juan Xiong & Yuanjiao Du & Yue Cao & Wei-Ke Ji, 2021. "An ESCRT-dependent step in fatty acid transfer from lipid droplets to mitochondria through VPS13D−TSG101 interactions," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-21525-5
    DOI: 10.1038/s41467-021-21525-5
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    Cited by:

    1. Zhen Yuan & Kun Cai & Jiajia Li & Ruifeng Chen & Fuhai Zhang & Xuan Tan & Yaming Jiu & Haishuang Chang & Bing Hu & Weiyi Zhang & Binbin Ding, 2024. "ATG14 targets lipid droplets and acts as an autophagic receptor for syntaxin18-regulated lipid droplet turnover," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    2. Lingxiu Kong & Qingjie Bai & Cuicui Li & Qiqin Wang & Yanfeng Wang & Xintian Shao & Yongchun Wei & Jiarao Sun & Zhenjie Yu & Junling Yin & Bin Shi & Hongbao Fang & Xiaoyuan Chen & Qixin Chen, 2024. "Molecular probes for tracking lipid droplet membrane dynamics," Nature Communications, Nature, vol. 15(1), pages 1-12, December.

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