Jingru Wang1, Na Fang1, Juan Xiong2, Yuanjiao Du1, Yue Cao1, Wei-Ke Ji3. 1. Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. 2. Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. 3. Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. J_WK@hust.edu.cn.
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.
Upon starvation, cells rewire their metabolism, switching from pan class="Chemical">glucose-based metabolism to mitochondrial oxidation of pan class="Chemical">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 humanVPS13D 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: Hong Wang; Urmilla Sreenivasan; Hong Hu; Andrew Saladino; Brian M Polster; Linda M Lund; Da-Wei Gong; William C Stanley; Carole Sztalryd Journal: J Lipid Res Date: 2011-08-31 Impact factor: 5.922
Authors: Ilan Y Benador; Michaela Veliova; Kiana Mahdaviani; Anton Petcherski; Jakob D Wikstrom; Essam A Assali; Rebeca Acín-Pérez; Michaël Shum; Marcus F Oliveira; Saverio Cinti; Carole Sztalryd; William D Barshop; James A Wohlschlegel; Barbara E Corkey; Marc Liesa; Orian S Shirihai Journal: Cell Metab Date: 2018-04-03 Impact factor: 27.287
Authors: Albert Herms; Marta Bosch; Babu J N Reddy; Nicole L Schieber; Alba Fajardo; Celia Rupérez; Andrea Fernández-Vidal; Charles Ferguson; Carles Rentero; Francesc Tebar; Carlos Enrich; Robert G Parton; Steven P Gross; Albert Pol Journal: Nat Commun Date: 2015-05-27 Impact factor: 14.919
Authors: Alex M Valm; Sarah Cohen; Wesley R Legant; Justin Melunis; Uri Hershberg; Eric Wait; Andrew R Cohen; Michael W Davidson; Eric Betzig; Jennifer Lippincott-Schwartz Journal: Nature Date: 2017-05-24 Impact factor: 49.962
Authors: Luca Scorrano; Maria Antonietta De Matteis; Scott Emr; Francesca Giordano; György Hajnóczky; Benoît Kornmann; Laura L Lackner; Tim P Levine; Luca Pellegrini; Karin Reinisch; Rosario Rizzuto; Thomas Simmen; Harald Stenmark; Christian Ungermann; Maya Schuldiner Journal: Nat Commun Date: 2019-03-20 Impact factor: 14.919
Authors: Ruben Grillo-Risco; Laura Pereira; M Carmen Soler-Vázquez; Inés Barahona; Patricia Rada; Silvia Calero-Pérez; Laura María LaIglesia; María J Moreno-Aliaga; Laura Herrero; Dolors Serra; Carmelo García-Monzon; Águeda González-Rodriguez; Jesús Balsinde; Francisco García-García; M Pilar Valdecantos; Ángela M Valverde Journal: Cell Death Differ Date: 2022-06-09 Impact factor: 15.828
Authors: Stephanie Vrijsen; Céline Vrancx; Mara Del Vecchio; Johannes V Swinnen; Patrizia Agostinis; Joris Winderickx; Peter Vangheluwe; Wim Annaert Journal: Front Neurosci Date: 2022-06-21 Impact factor: 5.152