Molecular analysis of Shy1/Surf1 function in early steps of cytochrome c oxidase assembly

• Applicant: Professor Dr. Peter Rehling
• Subject Area: Biochemistry
• Term: from 2008 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 88204809

• Final Report Year: 2018

Final Report Abstract

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.

Publications

• (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.
  
• (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.
  
• (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.
  
• (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.
  
• (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.
  
• (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.
  
• (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.
  
• (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.
  
• (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.
  
• (2015) Integrating mitochondrial translation into the cellular context. Nature Rev. Mol. Cell Biol. 16: 586-592
  Richter-Dennerlein, R., Dennerlein, S., and Rehling, P.
  
• (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.
  
• (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.
  
• (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.
  
• (2017) Plasticity of mitochondrial translation. Trends Cell. Biol. 27: 712-721
  Dennerlein, S., Wang, C., and Rehling, P.