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EMBO Mol Med. 2018 Nov;10(11). pii: e9060. doi: 10.15252/emmm.201809060.

OXA1L mutations cause mitochondrial encephalopathy and a combined oxidative phosphorylation defect.

Author information

1
Wellcome Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, UK.
2
Institute for Cell and Molecular Biosciences, Newcastle University Institute for Ageing, Newcastle University, Newcastle upon Tyne, UK.
3
Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Melbourne, Vic., Australia.
4
Department of Biochemistry and Molecular Biology and The Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Vic., Australia.
5
Pathology Department, Hospital Sant Joan de Déu, CIBERER, Barcelona, Spain.
6
Neuromuscular Unit, Neuropaediatrics Department, Hospital Sant Joan de Déu, CIBERER - ISCIII, Barcelona, Spain.
7
Oxford Medical Genetics Laboratories, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
8
Institute of Biotechnology, University of Helsinki, Helsinki, Finland.
9
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
10
Wellcome Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, UK robert.taylor@ncl.ac.uk.

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.

KEYWORDS:

OXPHOS ; OXA1L; encephalopathy; insertase; mitochondria

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