Project 13:
In vivo profiling of authentic cytosolic targeting routes of mitochondrial precursor proteins
Nora Vögtle
E-Mail: n.voegtle@zmbh.uni-heidelberg.de
Phone: +49 6221-54-6866
Zentrum für Molekulare Biologie (ZMBH)
Heidelberg University
Günter Kramer
E-Mail: g.kramer@zmbh.uni-heidelberg.de
Phone: +49 6221-54-6878
Zentrum für Molekulare Biologie (ZMBH)
Heidelberg University
Abstract
Import of nuclear encoded precursor proteins into mitochondria was traditionally viewed as a post-translational process, but growing evidence now suggests the existence of two or more alternative, translation-coupled import routes. In this project, we will perform a proteome-wide analysis of the substrate spectrum of each import route. We will identify cytosolic factors involved in the triaging of nascent precursors, reveal the principles of substrate recognition, study the molecular interplay of the targeting and the translation machinery and explore how function and robustness of the system may be perturbed by cytosolic and mitochondrial stress.
Project-relevant publications
Minoia M, Quintana-Cordero J, Jetzinger K, Kotan IE, Turnbull KJ, Ciccarelli M, Masser AE, Liebers D, Gouarin E, Czech M, Hauryliuk V, Bukau B, Kramer G, Andréasson C (2024) Chp1 is a dedicated chaperone at the ribosome that safeguards eEF1A biogenesis. Nat Commun. 15(1):1382.
Günnigmann M, Koubek J, Kramer G, Bukau B (2023) Selective ribosome profiling as a tool to study interactions of translating ribosomes in mammalian cells. Methods Enzymol. 684:1-38.
Eismann L, Fijalkowski I, Galmozzi CV, Koubek J, Tippmann F, Van Damme P, Kramer G (2022) Selective ribosome profiling reveals a role for SecB in the co-translational inner membrane protein biogenesis. Cell Rep. 41(10):111776.
Bertolini M, Fenzl K, Kats I, Wruck F, Tippmann F, Schmitt J, Auburger JJ, Tans S, Bukau B, Kramer G (2021) Interactions between nascent proteins translated by adjacent ribosomes drive homomer assembly. Science. 371(6524):57-64.
Poveda-Huertes D, Taskin AA, Dhaouadi I, Myketin L, Marada A, Habernig L, Büttner S, Vögtle FN (2021) Increased mitochondrial protein import and cardiolipin remodelling upon early mtUPR. PLoS Genet. 17(7):e1009664.
Walter C, Marada A, Suhm T, Ernsberger R, Muders V, Kücükköse C, Sánchez-Martín P, Hu Z, Aich A, Loroch S, Solari FA, Poveda-Huertes D, Schwierzok A, Pommerening H, Matic S, Brix J, Sickmann A, Kraft C, Dengjel J, Dennerlein S, Brummer T, Vögtle FN, Meisinger C (2021) Global kinome profiling reveals DYRK1A as critical activator of the human mitochondrial import machinery. Nat Commun. 12(1):4284.
Poveda-Huertes D, Matic S, Marada A, Habernig L, Licheva M, Myketin L, Gilsbach R, Tosal-Castano S, Papinski D, Mulica P, Kretz O, Kücükköse C, Taskin AA, Hein L, Kraft C, Büttner S, Meisinger C, Vögtle FN (2020) An early mtUPR: redistribution of the nuclear transcription factor Rox1 to mitochondria protects against Intramitochondrial proteotoxic aggregates. Mol Cell. 77(1):180-188.e9.
Galmozzi CV, Merker D, Friedrich UA, Döring K, Kramer G (2019) Selective ribosome profiling to study interactions of translating ribosomes in yeast. Nat Protoc. 14(8):2279-2317.
Shiber A, Döring K, Friedrich U, Klann K, Merker D, Zedan M, Tippmann F, Kramer G, Bukau B (2018) Cotranslational assembly of protein complexes in eukaryotes revealed by ribosome profiling. Nature. 561(7722):268-272.
Vögtle FN, Brändl B, Larson A, Pendziwiat M, Friederich MW, White SM, Basinger A, Kücükköse C, Muhle H, Jähn JA, Keminer O, Helbig KL, Delto CF, Myketin L, Mossmann D, Burger N, Miyake N, Burnett A, van Baalen A, Lovell MA, Matsumoto N, Walsh M, Yu HC, Shinde DN, Stephani U, Van Hove JLK, Müller FJ, Helbig I (2018) Mutations in PMPCB Encoding the Catalytic Subunit of the Mitochondrial Presequence Protease Cause Neurodegeneration in Early Childhood. Am J Hum Genet. 102(4):557-573.
Vögtle FN, Burkhart JM, Gonczarowska-Jorge H, Kücükköse C, Taskin AA, Kopczynski D, Ahrends R, Mossmann D, Sickmann A, Zahedi RP, Meisinger C (2017) Landscape of submitochondrial protein distribution. Nat Commun. 8(1):290.
Mossmann D, Vögtle FN, Taskin AA, Teixeira PF, Ring J, Burkhart JM, Burger N, Pinho CM, Tadic J, Loreth D, Graff C, Metzger F, Sickmann A, Kretz O, Wiedemann N, Zahedi RP, Madeo F, Glaser E, Meisinger C (2014) Amyloid-β peptide induces mitochondrial dysfunction by inhibition of preprotein maturation. Cell Metab. 20(4):662-9.
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