Mutations in the gene encoding C8orf38 block complex I assembly by inhibiting production of the mitochondria-encoded subunit ND1 |
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Authors: | McKenzie Matthew Tucker Elena J Compton Alison G Lazarou Michael George Christa Thorburn David R Ryan Michael T |
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Institution: | 1 Centre for Reproduction and Development, Monash Institute of Medical Research, Clayton 3168, Australia2 Murdoch Childrens Research Institute and Victorian Clinical Genetics Service Pathology, Royal Children's Hospital, Parkville 3052, Australia3 Department of Paediatrics, University of Melbourne, Melbourne 3010, Australia4 National Institute of Neurological Disorders and Stroke, Bethesda, MD 20892, USA5 Department of Biochemistry, La Trobe University, Melbourne 3086, Australia6 ARC Centre of Excellence for Coherent X-ray Science, La Trobe University, Melbourne 3086, Australia |
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Abstract: | The assembly of complex I (NADH-ubiquinone oxidoreductase) is a complicated process, requiring the integration of 45 subunits encoded by both nuclear and mitochondrial DNAs into a structure of approximately 1 MDa. A number of “assembly factors” that aid complex I biogenesis have recently been described, including C8orf38. This protein was identified as an assembly factor by its evolutionary conservation in organisms containing complex I and by a C8orf38 mutation in a patient presenting with Leigh syndrome and isolated complex I deficiency. In this report, we have undertaken the characterization of C8orf38 and its role in complex I assembly. Analysis of mitochondria from fibroblasts of a patient harboring a C8orf38 mutation showed almost undetectable levels of steady-state complex I and defective biogenesis of the mtDNA-encoded subunit ND1. Complementation with wild-type C8orf38 restored the levels of both ND1 and complex I, confirming the C8orf38 mutation as the cause of the complex I defect in the patient. In the absence of ND1 in patient cells, early- and mid-stage intermediate complexes were still formed; however, assembly of late-stage intermediates was impaired, indicating a convergence point in the assembly process. While C8orf38 appears to behave at a step in complex I biogenesis similar to that of the assembly factor C20orf7, complementation studies showed that both proteins are required for ND1 synthesis/stabilization. We conclude that C8orf38 is a crucial factor required for the translation and/or integration of ND1 into an early-stage assembly intermediate and that mutation of C8orf38 disrupts the initial stages of complex I biogenesis. |
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