Role of lipid transfer proteins and membrane contact sites for intramitochondrial lipid trafficking
Final Report Abstract
Mitochondria serve as metabolic and signaling hubs whose functions must be maintained in steady-state conditions and be adopted to meet cellular metabolic demands. They comprise double-layered biological membranes housing essential protein machineries whose functions depend on their lipid environment in these membranes. Not surprisingly, recent studies increasingly denote the importance of membrane lipid biogenesis in the maintenance and adaptation of mitochondrial activities. However, until recently, it remained obscure how mitochondria exchange lipids and its precursors and communicate with other cellular compartments. In this project, we have analysed intramitochondrial lipid trafficking, structurally characterized lipid transfer proteins involved and examined the role of membrane contact sites facilitated by MICOS complexes. Ups2-Mdm35/PRELID3b-TRIAP1 complexes were identified and structurally characterized as conserved, intramitochondrial lipid transfer proteins for PS, which is converted into PE at the mitochondrial IM. Close contacts between mitochondrial membranes assisted by MICOS were found to enable PE synthesis at OM and PE export to the ER. Fine-tuning of PE level maintains physiochemical properties of the IM including cristae morphogenesis. Moreover, we discovered that PE levels control the activity of the mitochondrial protease YME1L, which broadly reshapes the mitochondrial proteome in hypoxic and starved cells. mTORC1 inhibition initiates a phospholipid signaling cascade which lowers mitochondrial PE and activates YME1L mediated proteolysis. Finally, we found an unexpected link between intramitochondrial lipid biogenesis and cellular stress signaling cascades. Together, our experiments did not only deepen our understanding of intramitochondrial phospholipid transport and biogenesis, but also revealed unexpected links of membrane lipid homeostasis to mitochondrial proteostasis and intracellular signaling.
Publications
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(2015) Structural insight into the TRIAP1/PRELI-like domain family of mitochondrial phospholipid transfer complexes. EMBO Rep. 16:824-835
Miliara, X., J.A. Garnett, T. Tatsuta, F. Abid Ali, H. Baldie, I. Perez-Dorado, P. Simpson, E. Yague, T. Langer, and S. Matthews
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(2016) MICOS and phospholipid transfer by Ups2-Mdm35 organize membrane lipid synthesis in mitochondria. J. Cell Biol. 213:525-534
Aaltonen, M.J., J.R. Friedman, C. Osman, B. Salin, J.P. di Rago, J. Nunnari, T. Langer, and T. Tatsuta
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(2017) Intramitochondrial phospholipid trafficking. Biochim Biophys Acta. 1862:81-89
Tatsuta, T., and T. Langer
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(2017). Quantitative Analysis of Glycerophospholipids in Mitochondria by Mass Spectrometry. Methods Mol Biol. 1567:79-103
Tatsuta, T.
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(2019) Lipid signalling drives proteolytic rewiring of mitochondria by YME1L. Nature. 575:361- 365
MacVicar, T., Y. Ohba, H. Nolte, F.C. Mayer, T. Tatsuta, H.G. Sprenger, B. Lindner, Y. Zhao, J. Li, C. Bruns, M. Kruger, M. Habich, J. Riemer, R. Schwarzer, M. Pasparakis, S. Henschke, J.C. Bruning, N. Zamboni, and T. Langer
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(2019) Structural determinants of lipid specificity within Ups/PRELI lipid transfer proteins. Nat. Commun. 10:1130
Miliara, X., T. Tatsuta, J.L. Berry, S.L. Rouse, K. Solak, D.S. Chorev, D. Wu, C.V. Robinson, S. Matthews, and T. Langer
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(2021) Disturbed intramitochondrial phosphatidic acid transport impairs cellular stress signaling. J. Biol. Chem. 296:100335
Eiyama, A., M.J. Aaltonen, H. Nolte, T. Tatsuta, and T. Langer
