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David A Stroud, Megan J Maher, Caroline Lindau, F-Nora Vögtle, Ann E Frazier, Elliot Surgenor, Hayley Mountford, Abeer P Singh, Matteo Bonas, Silke Oeljeklaus, Bettina Warscheid, Chris Meisinger, David R Thorburn, Michael T Ryan
Biogenesis of complex IV of the mitochondrial respiratory chain requires assembly factors for subunit maturation, co-factor attachment and stabilization of intermediate assemblies. A pathogenic mutation in COA6, leading to substitution of a conserved tryptophan for a cysteine residue, results in a loss of complex IV activity and cardiomyopathy. Here, we demonstrate that the complex IV defect correlates with a severe loss in complex IV assembly in patient heart but not fibroblasts. Complete loss of COA6 activity using gene editing in HEK293T cells resulted in a profound growth defect due to complex IV deficiency, caused by impaired biogenesis of the copper-bound mitochondrial DNA-encoded subunit COX2 and subsequent accumulation of complex IV assembly intermediates...
October 1, 2015: Human Molecular Genetics
David Pacheu-Grau, Bettina Bareth, Jan Dudek, Lisa Juris, F-Nora Vögtle, Mirjam Wissel, Scot C Leary, Sven Dennerlein, Peter Rehling, Markus Deckers
Three mitochondria-encoded subunits form the catalytic core of cytochrome c oxidase, the terminal enzyme of the respiratory chain. COX1 and COX2 contain heme and copper redox centers, which are integrated during assembly of the enzyme. Defects in this process lead to an enzyme deficiency and manifest as mitochondrial disorders in humans. Here we demonstrate that COA6 is specifically required for COX2 biogenesis. Absence of COA6 leads to fast turnover of newly synthesized COX2 and a concomitant reduction in cytochrome c oxidase levels...
June 2, 2015: Cell Metabolism
Fabian Baertling, Mariel A M van den Brand, Jozef L Hertecant, Aisha Al-Shamsi, Lambert P van den Heuvel, Felix Distelmaier, Ertan Mayatepek, Jan A Smeitink, Leo G J Nijtmans, Richard J T Rodenburg
COA6/C1ORF31 is involved in cytochrome c oxidase (complex IV) biogenesis. We present a new pathogenic COA6 variant detected in a patient with neonatal hypertrophic cardiomyopathy and isolated complex IV deficiency. For the first time, clinical details about a COA6-deficient patient are given and patient fibroblasts are functionally characterized: COA6 protein is undetectable and steady-state levels of complex IV and several of its subunits are reduced. The monomeric COX1 assembly intermediate accumulates. Using pulse-chase experiments, we demonstrate an increased turnover of mitochondrial encoded complex IV subunits...
January 2015: Human Mutation
Alok Ghosh, Prachi P Trivedi, Shrishiv A Timbalia, Aaron T Griffin, Jennifer J Rahn, Sherine S L Chan, Vishal M Gohil
Mitochondrial respiratory chain biogenesis is orchestrated by hundreds of assembly factors, many of which are yet to be discovered. Using an integrative approach based on clues from evolutionary history, protein localization and human genetics, we have identified a conserved mitochondrial protein, C1orf31/COA6, and shown its requirement for respiratory complex IV biogenesis in yeast, zebrafish and human cells. A recent next-generation sequencing study reported potential pathogenic mutations within the evolutionarily conserved Cx₉CxnCx₁₀C motif of COA6, implicating it in mitochondrial disease biology...
July 1, 2014: Human Molecular Genetics
F-Nora Vögtle, Julia M Burkhart, Sanjana Rao, Carolin Gerbeth, Jens Hinrichs, Jean-Claude Martinou, Agnieszka Chacinska, Albert Sickmann, René P Zahedi, Chris Meisinger
The intermembrane space (IMS) represents the smallest subcompartment of mitochondria. Nevertheless, it plays important roles in the transport and modification of proteins, lipids, and metal ions and in the regulation and assembly of the respiratory chain complexes. Moreover, it is involved in many redox processes and coordinates key steps in programmed cell death. A comprehensive profiling of IMS proteins has not been performed so far. We have established a method that uses the proapoptotic protein Bax to release IMS proteins from isolated mitochondria, and we profiled the protein composition of this compartment...
December 2012: Molecular & Cellular Proteomics: MCP
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