Crosstalk between mitochondrial and lipid biogenesis

• Applicant: Professor Dr. Thomas Becker
• Subject Area: Biochemistry
• Term: from 2015 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 269424439

• Final Report Year: 2024

Final Report Abstract

Mitochondrial biogenesis and functions depend on the import and biosynthesis of lipids and proteins. In the model organism baker´s Saccharomyces cerevisiae, mitochondria have to import about 1000 proteins from the cytosol and the majority of phospholipids from the endoplasmic reticulum (ER). In this project, we investigated the cross-talk between mitochondrial protein and lipid biogenesis. First, we analysed the impact of major phospholipids on protein import. We found that the individual depletion of the major phospholipids cardiolipin, phosphatidylethanolamine and phosphatidylcholine differentially affect integrity and function of mitochondrial protein translocases and respiratory chain. Second, we studied the molecular cross-talk between protein import and organelle contact sites. Mdm10 binds to the sorting and assembly machinery (SAM complex) and to the ER-mitochondria encounter structure (ERMES) that ensures lipid trafficking between the ER and mitochondria. Using site-directed mutagenesis, we showed that Mdm10 at the SAM complex promotes the assembly of the translocase of the outer mitochondrial membrane (TOM complex), while Mdm10 at the ERMES complex maintains normal lipid levels and mitochondrial morphology. We performed a high-resolution complexome profiling of yeast mitochondria and identified the small protein Mco6 as interaction partner of the SAM-Mdm10 complex. Our data revealed that Mco6 cooperates with Mdm10 to promote the assembly of the TOM complex. Finally, we found an interaction of the mitochondrial import (MIM complex) machinery of the outer membrane to the short chain dehydrogenase Ayr1 that is involved in lipid metabolism in the ER and lipid droplets. We found that Ayr1 promotes the association of lipid droplets to the mitochondrial surface and modulates their degradation. Thus, the interaction of Ayr1 and the MIM complex represents a novel link between protein import and lipid homeostasis. In conclusion, protein import is closely linked via organellar contact sites to lipid trafficking to mitochondria.

Publications

• Phosphatidylcholine Affects the Role of the Sorting and Assembly Machinery in the Biogenesis of Mitochondrial β-Barrel Proteins. Journal of Biological Chemistry, 290(44), 26523-26532.
  Schuler, Max-Hinderk; Di Bartolomeo Francesca; Böttinger, Lena; Horvath, Susanne E.; Wenz, Lena-Sophie; Daum, Günther & Becker, Thomas
  
• The fusogenic lipid phosphatidic acid promotes the biogenesis of mitochondrial outer membrane protein Ugo1. Journal of Cell Biology, 210(6), 951-960.
  Vögtle, F.-Nora; Keller, Michael; Taskin, Asli A.; Horvath, Susanne E.; Guan, Xue Li; Prinz, Claudia; Opalińska, Magdalena; Zorzin, Carina; van der Laan, Martin; Wenk, Markus R.; Schubert, Rolf; Wiedemann, Nils; Holzer, Martin & Meisinger, Chris
  
• Phosphatidylcholine Affects Inner Membrane Protein Translocases of Mitochondria. Journal of Biological Chemistry, 291(36), 18718-18729.
  Schuler, Max-Hinderk; Di Bartolomeo, Francesca; Mårtensson, Christoph U.; Daum, Günther & Becker, Thomas
  
• Separating mitochondrial protein assembly and endoplasmic reticulum tethering by selective coupling of Mdm10. Nature Communications, 7(1).
  Ellenrieder, Lars; Opaliński, Łukasz; Becker, Lars; Krüger, Vivien; Mirus, Oliver; Straub, Sebastian P.; Ebell, Katharina; Flinner, Nadine; Stiller, Sebastian B.; Guiard, Bernard; Meisinger, Chris; Wiedemann, Nils; Schleiff, Enrico; Wagner, Richard; Pfanner, Nikolaus & Becker, Thomas
  
• Definition of a High-Confidence Mitochondrial Proteome at Quantitative Scale. Cell Reports, 19(13), 2836-2852.
  Morgenstern, Marcel; Stiller, Sebastian B.; Lübbert, Philipp; Peikert, Christian D.; Dannenmaier, Stefan; Drepper, Friedel; Weill, Uri; Höß, Philipp; Feuerstein, Reinhild; Gebert, Michael; Bohnert, Maria; van der Laan, Martin; Schuldiner, Maya; Schütze, Conny; Oeljeklaus, Silke; Pfanner, Nikolaus; Wiedemann, Nils & Warscheid, Bettina
  
• Effects of lipids on mitochondrial functions. Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids, 1862(1), 102-113.
  Mårtensson, Christoph U.; Doan, Kim Nguyen & Becker, Thomas
  
• Identification of new channels by systematic analysis of the mitochondrial outer membrane. Journal of Cell Biology, 216(11), 3485-3495.
  Krüger, Vivien; Becker, Thomas; Becker, Lars; Montilla-Martinez, Malayko; Ellenrieder, Lars; Vögtle, F.-Nora; Meyer, Helmut E.; Ryan, Michael T.; Wiedemann, Nils; Warscheid, Bettina; Pfanner, Nikolaus; Wagner, Richard & Meisinger, Chris
  
• Membrane protein insertion through a mitochondrial β-barrel gate. Science, 359(6373).
  Höhr, Alexandra I. C.; Lindau, Caroline; Wirth, Christophe; Qiu, Jian; Stroud, David A.; Kutik, Stephan; Guiard, Bernard; Hunte, Carola; Becker, Thomas; Pfanner, Nikolaus & Wiedemann, Nils
  
• Phospholipid ebb and flow makes mitochondria go. Journal of Cell Biology, 219(8).
  Acoba, Michelle Grace; Senoo, Nanami & Claypool, Steven M.
  
• Structural insight into mitochondrial β-barrel outer membrane protein biogenesis. Nature Communications, 11(1).
  Diederichs, Kathryn A.; Ni, Xiaodan; Rollauer, Sarah E.; Botos, Istvan; Tan, Xiaofeng; King, Martin S.; Kunji, Edmund R. S.; Jiang, Jiansen & Buchanan, Susan K.
  
• The Mitochondrial Import Complex MIM Functions as Main Translocase for α-Helical Outer Membrane Proteins. Cell Reports, 31(4), 107567.
  Doan, Kim Nguyen; Grevel, Alexander; Mårtensson, Christoph U.; Ellenrieder, Lars; Thornton, Nicolas; Wenz, Lena-Sophie; Opaliński, Łukasz; Guiard, Bernard; Pfanner, Nikolaus & Becker, Thomas
  
• Emr1 regulates the number of foci of the endoplasmic reticulum-mitochondria encounter structure complex. Nature Communications, 12(1).
  Rasul, Faiz; Zheng, Fan; Dong, Fenfen; He, Jiajia; Liu, Ling; Liu, Wenyue; Cheema, Javairia Yousuf; Wei, Wenfan & Fu, Chuanhai
  
• Mitochondrial sorting and assembly machinery operates by β-barrel switching. Nature, 590(7844), 163-169.
  Takeda, Hironori; Tsutsumi, Akihisa; Nishizawa, Tomohiro; Lindau, Caroline; Busto, Jon V.; Wenz, Lena-Sophie; Ellenrieder, Lars; Imai, Kenichiro; Straub, Sebastian P.; Mossmann, Waltraut; Qiu, Jian; Yamamori, Yu; Tomii, Kentaro; Suzuki, Junko; Murata, Takeshi; Ogasawara, Satoshi; Nureki, Osamu; Becker, Thomas; Pfanner, Nikolaus ... & Endo, Toshiya
  
• Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context. Cell Metabolism, 33(12), 2464-2483.e18.
  Morgenstern, Marcel; Peikert, Christian D.; Lübbert, Philipp; Suppanz, Ida; Klemm, Cinzia; Alka, Oliver; Steiert, Conny; Naumenko, Nataliia; Schendzielorz, Alexander; Melchionda, Laura; Mühlhäuser, Wignand W.D.; Knapp, Bettina; Busch, Jakob D.; Stiller, Sebastian B.; Dannenmaier, Stefan; Lindau, Caroline; Licheva, Mariya; Eickhorst, Christopher; Galbusera, Riccardo ... & Warscheid, Bettina
  
• Role of the TOM Complex in Protein Import into Mitochondria: Structural Views. Annual Review of Biochemistry, 91(1), 679-703.
  Araiso, Yuhei; Imai, Kenichiro & Endo, Toshiya
  
• A multipoint guidance mechanism for β-barrel folding on the SAM complex. Nature Structural & Molecular Biology, 30(2), 176-187.
  Takeda, Hironori; Busto, Jon V.; Lindau, Caroline; Tsutsumi, Akihisa; Tomii, Kentaro; Imai, Kenichiro; Yamamori, Yu; Hirokawa, Takatsugu; Motono, Chie; Ganesan, Iniyan; Wenz, Lena-Sophie; Becker, Thomas; Kikkawa, Masahide; Pfanner, Nikolaus; Wiedemann, Nils & Endo, Toshiya
  
• Mitochondrial complexome reveals quality-control pathways of protein import. Nature, 614(7946), 153-159.
  Schulte, Uwe; den Brave, Fabian; Haupt, Alexander; Gupta, Arushi; Song, Jiyao; Müller, Catrin S.; Engelke, Jeannine; Mishra, Swadha; Mårtensson, Christoph; Ellenrieder, Lars; Priesnitz, Chantal; Straub, Sebastian P.; Doan, Kim Nguyen; Kulawiak, Bogusz; Bildl, Wolfgang; Rampelt, Heike; Wiedemann, Nils; Pfanner, Nikolaus; Fakler, Bernd & Becker, Thomas
  
• Mitochondrial protein transport: Versatility of translocases and mechanisms. Molecular Cell, 83(6), 890-910.
  Busch, Jakob D.; Fielden, Laura F.; Pfanner, Nikolaus & Wiedemann, Nils
  
• Identification of MIMAS, a multifunctional mega-assembly integrating metabolic and respiratory biogenesis factors of mitochondria. Cell Reports, 43(3), 113772.
  Horten, Patrick; Song, Kuo; Garlich, Joshua; Hardt, Robert; Colina-Tenorio, Lilia; Horvath, Susanne E.; Schulte, Uwe; Fakler, Bernd; van der Laan, Martin; Becker, Thomas; Stuart, Rosemary A.; Pfanner, Nikolaus & Rampelt, Heike
  
• Mitochondrial complexome and import network. Trends in Cell Biology, 34(7), 578-594.
  den, Brave Fabian; Schulte, Uwe; Fakler, Bernd; Pfanner, Nikolaus & Becker, Thomas
  
• Role of the small protein Mco6 in the mitochondrial sorting and assembly machinery. Cell Reports, 43(3), 113805.
  Busto, Jon V.; Ganesan, Iniyan; Mathar, Hannah; Steiert, Conny; Schneider, Eva F.; Straub, Sebastian P.; Ellenrieder, Lars; Song, Jiyao; Stiller, Sebastian B.; Lübbert, Philipp; Chatterjee, Ritwika; Elsaesser, Jana; Melchionda, Laura; Schug, Christina; den Brave, Fabian; Schulte, Uwe; Klecker, Till; Kraft, Claudine; Fakler, Bernd ... & Wiedemann, Nils