Molekulare Analyse der Funktionen von Shy1/SURF1 in den frühen Schritten der Cytochrom c Oxidase Assemblierung
Zusammenfassung der Projektergebnisse
SURF1 is highly conserved from bacteria to man and loss of SURF1 function leads to cytochrome c oxidase deficiency. It is currently assumed that SURF1 and its orthologs play a role in early steps of cytochrome c oxidase biogenesis and are required for the initial assembly steps of the mitochondrially-encoded Cox1, the central catalytic subunit of the complex. Our analyses assessed the function of this protein in the biogenesis of human and yeast cytochrome c oxidase assembly. In the course of these studies, we were able to identify new proteins that are critical for regulation of Cox1 translation in mitochondria. We defined assembly stages and provided insight into the quality control process for newly made Cox1. In the course of our studies, we found new insight into how heme is inserted into Cox1 and sharpened the view on a feedback regulatory cycle that adapts the amount of Cox1 to the physiological requirements. The translation of our work into the human system provided us with new proteins involved in COX1 assembly in human. Some of these proteins have been linked to human neuromuscular disorders. Our findings provided insight into how pathogenic mutation lead to malfunction of SURF1 and provided understanding as to how nuclear-encoded proteins are directed to mitochondrial-encoded partner proteins. Most importantly, we learned that in human mitochondria translation is coupled to respiratory chain assembly.
Projektbezogene Publikationen (Auswahl)
- (2010). Coa3 and Cox14 are essential for negative feedback regulation of COX1 translation in mitochondria. J. Cell Biol. 191: 141-154
Mick, D.U, Vukotic, M., Piechura, H., Meyer, H.E., Warscheid, B., Deckers, M., and Rehling, P.
(Siehe online unter https://dx.doi.org/10.1083/jcb.201007026) - (2011) Inventory control: cytochrome c oxidase assembly regulates mitochondrial translation. Nature Rev. Mol. Cell Biol. 12: 14-20
Mick, D.U., Fox, T.D, and Rehling, P.
(Siehe online unter https://dx.doi.org/10.1038/nrm3029) - (2011), Mimicking a SURF1 allele reveals uncoupling of cytochrome c oxidase assembly from translational regulation in yeast. Hum. Mol. Genet. 20: 2379-2393
Reinhold, R., Bareth, B., Balleininger, M., Wissel, M., Rehling, P., and Mick, D.U.
(Siehe online unter https://dx.doi.org/10.1093/hmg/ddr145) - (2012) MITRAC links mitochondrial protein translocation to respiratory-chain assembly and translational regulation. CELL 151: 1528-1541
Mick, D.U., Dennerlein, S., Wiese, H., Reinhold, R., Pacheu-Grau, D., Lorenzi, I., Sasarman, F., Weraarpachai, W., Shoubridge, E.A., Warscheid, B., and Rehling, P.
(Siehe online unter https://doi.org/10.1016/j.cell.2012.11.053) - (2012) Oxa1-ribosome complexes coordinate the assembly of cytochrome c oxidase in mitochondria. J. Biol. Chem. 287:34484-34493
Keil, M., Bareth, B., Woellhaf, M.M., Peleh, V., Prestele, M. Rehling, P., and Herrmann, J.M.
(Siehe online unter https://doi.org/10.1074/jbc.M112.382630) - (2012). The mitochondrial Oxidase Assembly Protein 1 (Oxa1) Insertase Forms a Membrane Pore in Lipid Bilayers J. Biol. Chem. 287:33314-33326
Krüger, V., Deckers, M., Hildenbeutel, M., van der Laan, M., Hellmers, M., Decker, C., Preuss, M. Herrmann, J.M., Rehling, P., Wagner, R., and Meinecke, M.
(Siehe online unter https://doi.org/10.1074/jbc.M112.387563) - (2013) The heme a synthase Cox15 associates with cytochrome c oxidase assembly intermediates during Cox1 maturation. Mol. Cell. Biol. 33: 4128-4137
Bareth, B., Dennerlein, S., Mick, D.U., Nikolov, M., Urlaub, H., and Rehling, P.
(Siehe online unter https://doi.org/10.1128/MCB.00747-13) - (2014) The INA complex facilitates assembly of the peripheral stalk of the mitochondrial F1Fo-ATP synthase. EMBO J 33: 1624–1638
Lytovchenko, O., Naumenko, N., Oeljeklaus, S., Schmidt, B., Malsburg von der, K., Deckers, M., Warscheid, B., van der Laan, M., and Rehling, P.
(Siehe online unter https://doi.org/10.15252/embj.201488076) - (2015) Assembly of COX1 into cytochrome c oxidase of human mitochondria - at a glance. J. Cell Sci. 128: 833-837
Dennerlein, S., and Rehling, P.
(Siehe online unter https://doi.org/10.1242/jcs.161729) - (2015) Integrating mitochondrial translation into the cellular context. Nature Rev. Mol. Cell Biol. 16: 586-592
Richter-Dennerlein, R., Dennerlein, S., and Rehling, P.
(Siehe online unter https://doi.org/10.1038/nrm4051) - (2016) The ribosome-associated Mba1 escorts Cox2 from insertion machinery to maturing assembly intermediates. Mol. Cell. Biol. 36: 2782-2793
Lorenzi, I., Oeljeklaus, S., Ronsör, C., Bareth, B., Warscheid, B., Rehling, P., and Dennerlein, S.
(Siehe online unter https://doi.org/10.1128/MCB.00361-16) - (2016). Oms1 associates with cytochrome c oxidase assembly intermediates to stabilize newly synthesized Cox1. Mol. Biol. Cell 27: 1570-1580
Bareth, B., Nikolov, M., Lorenzi, I., Hildenbeutel, M., Mick, D.U., Helbig, C., Urlaub, H., Ott, M., Rehling, P., and Dennerlein, S.
(Siehe online unter https://doi.org/10.1091/mbc.E15-12-0811) - (2017) INA complex liaises the F1Fo-ATP synthase membrane motor modules. Nat Commun 8: 1237
Naumenko, N., Morgenstern, M., Rucktäschel, R., Warscheid, B. and Rehling, P.
(Siehe online unter https://doi.org/10.1038/s41467-017-01437-z) - (2017) Plasticity of mitochondrial translation. Trends Cell. Biol. 27: 712-721
Dennerlein, S., Wang, C., and Rehling, P.
(Siehe online unter https://doi.org/10.1016/j.tcb.2017.05.004)
