OXA1L mutations cause mitochondrial encephalopathy and a combined oxidative phosphorylation defect

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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 , A , Battersby , B J , Bonnen , P E , Ryan , M T , Chrzanowska-Lightowlers , Z M , Lightowlers , R N & Taylor , R W 2018 , ' OXA1L mutations cause mitochondrial encephalopathy and a combined oxidative phosphorylation defect ' , EMBO molecular medicine , vol. 10 , no. 11 , e9060 . https://doi.org/10.15252/emmm.201809060

Title: OXA1L mutations cause mitochondrial encephalopathy and a combined oxidative phosphorylation defect
Author: Thompson, Kyle; Mai, Nicole; Oláhová, Monika; Scialó, Filippo; Formosa, Luke E; Stroud, David A; Garrett, Madeleine; Lax, Nichola Z; Robertson, Fiona M; Jou, Cristina; Nascimento, Andres; Ortez, Carlos; Jimenez-Mallebrera, Cecilia; Hardy, Steven A; He, Langping; Brown, Garry K; Marttinen, Paula; McFarland, Robert; Sanz, Alberto; Battersby, Brendan J; Bonnen, Penelope E; Ryan, Michael T; Chrzanowska-Lightowlers, Zofia Ma; Lightowlers, Robert N; Taylor, Robert W
Contributor organization: Institute of Biotechnology
Doctoral Programme in Biomedicine
Doctoral Programme in Integrative Life Science
University Management
Date: 2018-11-01
Language: eng
Number of pages: 13
Belongs to series: EMBO molecular medicine
ISSN: 1757-4676
DOI: https://doi.org/10.15252/emmm.201809060
URI: http://hdl.handle.net/10138/299102
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.500507dup, 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.
Subject: OXPHOS
1182 Biochemistry, cell and molecular biology
Peer reviewed: Yes
Rights: cc_by
Usage restriction: openAccess
Self-archived version: publishedVersion

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