Thompson, K. et al. (2018) OXA 1L mutations cause mitochondrial encephalopathy and a combined oxidative phosphorylation defect. EMBO Molecular Medicine, 10(11), e9060. (doi: 10.15252/emmm.201809060) (PMID:30201738) (PMCID:PMC6220311)
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Abstract
OXA1, the mitochondrial member of the YidC/Alb3/Oxa1 membrane protein insertase family, is required for the assembly of oxidative phosphorylation complexes IV and V in yeast. However, depletion of human OXA1 (OXA1L) was previously reported to impair assembly of complexes I and V only. We report a patient presenting with severe encephalopathy, hypotonia and developmental delay who died at 5 years showing complex IV deficiency in skeletal muscle. Whole exome sequencing identified biallelic OXA1L variants (c.500_507dup, p.(Ser170Glnfs*18) and c.620G>T, p.(Cys207Phe)) that segregated with disease. Patient muscle and fibroblasts showed decreased OXA1L and subunits of complexes IV and V. Crucially, expression of wild‐type human OXA1L in patient fibroblasts rescued the complex IV and V defects. Targeted depletion of OXA1L in human cells or Drosophila melanogaster caused defects in the assembly of complexes I, IV and V, consistent with patient data. Immunoprecipitation of OXA1L revealed the enrichment of mtDNA‐encoded subunits of complexes I, IV and V. Our data verify the pathogenicity of these OXA1L variants and demonstrate that OXA1L is required for the assembly of multiple respiratory chain complexes.
Item Type: | Articles |
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Additional Information: | This work is supported by the Wellcome Centre for Mitochondrial Research (203105/Z/16/Z), the Medical Research Council (MRC) Centre for Translational Research in Neuromuscular Disease, Mitochondrial Disease Patient Cohort (UK) (G0800674), the Lily Foundation, The Barbour Foundation, the UK NIHR Biomedical Research Centre for Ageing and Age‐related disease award to the Newcastle upon Tyne Foundation Hospitals NHS Trust, the MRC/EPSRC Molecular Pathology Node, the UK NHS Highly Specialised Service for Rare Mitochondrial Disorders of Adults and Children, the National Institute of Neurological Disorders and Stroke of the National Institutes of Health (award number R01NS083726 to PEB), the Biotechnology and Biological Sciences Research Council (BB/M023311/1) and the Australian Mitochondria Disease Foundation (AMDF)). MTR and DAS were funded by the National Health & Medical Research Council (NHMRC) of Australia (Grants APP 1125390, 1107094, 1140906) and a Fellowship (1140851) to DAS. CJ‐M is funded by the Instituto de Salud Carlos III and the European Regional Development Fund (FEDER) grant CP09/00011. |
Status: | Published |
Refereed: | Yes |
Glasgow Author(s) Enlighten ID: | Sanz Montero, Professor Alberto |
Creator Roles: | |
Authors: | Thompson, K., Mai, N., Oláhová, M., Scialó, F., Formosa, L. E., Stroud, D. A., Garrett, M., Lax, N. Z., Robertson, F. M., Jou, C., Nascimento, A., Ortez, C., Jimenez‐Mallebrera, C., Hardy, S. A., He, L., Brown, G. K., Marttinen, P., McFarland, R., Sanz Montero, A., Battersby, B. J., Bonnen, P. E., Ryan, M. T., Chrzanowska‐Lightowlers, Z. M.A., Lightowlers, R. N., and Taylor, R. W. |
College/School: | College of Medical Veterinary and Life Sciences > School of Molecular Biosciences |
Journal Name: | EMBO Molecular Medicine |
Publisher: | EMBO Press |
ISSN: | 1757-4676 |
ISSN (Online): | 1757-4684 |
Published Online: | 10 September 2018 |
Copyright Holders: | Copyright © 2018 The Authors |
First Published: | First published in EMBO Molecular Medicine 10:e9060 |
Publisher Policy: | Reproduced under a Creative Commons License |
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