The transfer of phospholipids between the ER and mitochondria is critical for mitochondrial biogenesis. Mitochondria cannot synthesize many of the lipids they require for membrane biogenesis and yet there is little or no vesicular trafficking to mitochondria. It is thought that lipids are transferred from the ER to mitochondria by a poorly understood nonvesicular mechanism. This transport has been proposed to occur at regions where the ER and mitochondria are closely apposed. We have found that lipid synthesis at contacts between the ER and mitochondria (and other contact sites) promotes lipid exchange and are working to discover the mechanism. In a second project, we have identified a protein that facilitates contacts between the Golgi and the ER and facilitates ceramide transport. Ceramides are key intermediates in sphingolipid biosynthesis and potent signaling molecules. However, excess ceramide is toxic, causing growth arrest and apoptosis. We identified a novel mechanism by which cells prevent the toxic accumulation of ceramides; they promote nonvesicular ceramide transfer from the ER to the Golgi complex, where ceramides are converted to complex sphingolipids. We found that the yeast protein Nvj2p is an ER-Golgi tether that generates close contacts between these compartments and promotes the nonvesicular transfer of ceramides to the Golgi complex. The protein normally resides at contacts between the ER and other organelles but during ER stress it relocalizes to and increases ER-Golgi contacts. ER-Golgi contacts fail to form during ER stress in cells lacking Nvj2p. Our findings demonstrate that cells regulate ER-Golgi contacts in response to stress and reveal that nonvesicular ceramide transfer out of the ER prevents the build up of toxic amounts of ceramides. A third project focuses on sterol transport to the vacuole. We have found that sterol-enriched domains form on the vacuole membrane in response to various cellular stresses. The domains regulate the stress response. We are working to understand how sterol transport is mediated and have found that conserved class of lipid transport proteins is required. The mammalian homologues of these proteins are seem to perform the same function.

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16
Fiscal Year
2017
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U.S. National Inst Diabetes/Digst/Kidney
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Choudhary, Vineet; Golani, Gonen; Joshi, Amit S et al. (2018) Architecture of Lipid Droplets in Endoplasmic Reticulum Is Determined by Phospholipid Intrinsic Curvature. Curr Biol 28:915-926.e9
Lin, Cheng-Chao; Kurashige, Mahiro; Liu, Yi et al. (2018) A cleavage product of Polycystin-1 is a mitochondrial matrix protein that affects mitochondria morphology and function when heterologously expressed. Sci Rep 8:2743
Friedman, Jonathan R; Kannan, Muthukumar; Toulmay, Alexandre et al. (2018) Lipid Homeostasis Is Maintained by Dual Targeting of the Mitochondrial PE Biosynthesis Enzyme to the ER. Dev Cell 44:261-270.e6
Hayes, Matthew; Choudhary, Vineet; Ojha, Namrata et al. (2017) Fat storage-inducing transmembrane (FIT or FITM) proteins are related to lipid phosphatase/phosphotransferase enzymes. Microb Cell 5:88-103
Liu, Li-Ka; Choudhary, Vineet; Toulmay, Alexandre et al. (2017) An inducible ER-Golgi tether facilitates ceramide transport to alleviate lipotoxicity. J Cell Biol 216:131-147
Michaud, Morgane; Prinz, William A; Jouhet, Juliette (2017) Glycerolipid synthesis and lipid trafficking in plant mitochondria. FEBS J 284:376-390
Prinz, William A (2017) A cholesterol-sensing mechanism unfolds. J Biol Chem 292:19974-19975
Kannan, Muthukumar; Lahiri, Sujoy; Liu, Li-Ka et al. (2017) Phosphatidylserine synthesis at membrane contact sites promotes its transport out of the ER. J Lipid Res 58:553-562
Murley, Andrew; Yamada, Justin; Niles, Bradley J et al. (2017) Sterol transporters at membrane contact sites regulate TORC1 and TORC2 signaling. J Cell Biol 216:2679-2689
Kannan, Muthukumar; Sivaprakasam, Chinnarasu; Prinz, William A et al. (2016) Endoplasmic reticulum stress affects the transport of phosphatidylethanolamine from mitochondria to the endoplasmic reticulum in S.cerevisiae. Biochim Biophys Acta 1861:1959-1967

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