OXA1L mutations cause mitochondrial encephalopathy and a combined oxidative phosphorylation defect
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 re...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Springer Nature
2018-11-01
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| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.15252/emmm.201809060 |
| _version_ | 1797284653415006208 |
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| author | Kyle Thompson Nicole Mai Monika Oláhová Filippo Scialó Luke E Formosa David A Stroud Madeleine Garrett Nichola Z Lax Fiona M Robertson Cristina Jou Andres Nascimento Carlos Ortez Cecilia Jimenez‐Mallebrera Steven A Hardy Langping He Garry K Brown Paula Marttinen Robert McFarland Alberto Sanz Brendan J Battersby Penelope E Bonnen Michael T Ryan Zofia MA Chrzanowska‐Lightowlers Robert N Lightowlers Robert W Taylor |
| author_facet | Kyle Thompson Nicole Mai Monika Oláhová Filippo Scialó Luke E Formosa David A Stroud Madeleine Garrett Nichola Z Lax Fiona M Robertson Cristina Jou Andres Nascimento Carlos Ortez Cecilia Jimenez‐Mallebrera Steven A Hardy Langping He Garry K Brown Paula Marttinen Robert McFarland Alberto Sanz Brendan J Battersby Penelope E Bonnen Michael T Ryan Zofia MA Chrzanowska‐Lightowlers Robert N Lightowlers Robert W Taylor |
| author_sort | Kyle Thompson |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-07T17:51:29Z |
| format | Article |
| id | doaj.art-0d713560574b49dfa1120e2d8edbb05c |
| institution | Directory Open Access Journal |
| issn | 1757-4676 1757-4684 |
| language | English |
| last_indexed | 2024-03-07T17:51:29Z |
| publishDate | 2018-11-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj.art-0d713560574b49dfa1120e2d8edbb05c2024-03-02T13:58:00ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842018-11-011011n/an/a10.15252/emmm.201809060OXA1L mutations cause mitochondrial encephalopathy and a combined oxidative phosphorylation defectKyle Thompson0Nicole Mai1Monika Oláhová2Filippo Scialó3Luke E Formosa4David A Stroud5Madeleine Garrett6Nichola Z Lax7Fiona M Robertson8Cristina Jou9Andres Nascimento10Carlos Ortez11Cecilia Jimenez‐Mallebrera12Steven A Hardy13Langping He14Garry K Brown15Paula Marttinen16Robert McFarland17Alberto Sanz18Brendan J Battersby19Penelope E Bonnen20Michael T Ryan21Zofia MA Chrzanowska‐Lightowlers22Robert N Lightowlers23Robert W Taylor24Wellcome Centre for Mitochondrial Research Newcastle University Newcastle upon Tyne UKWellcome Centre for Mitochondrial Research Newcastle University Newcastle upon Tyne UKWellcome Centre for Mitochondrial Research Newcastle University Newcastle upon Tyne UKInstitute for Cell and Molecular Biosciences Newcastle University Institute for Ageing Newcastle University Newcastle upon Tyne UKDepartment of Biochemistry and Molecular Biology Monash Biomedicine Discovery Institute Monash University Melbourne Vic. AustraliaDepartment of Biochemistry and Molecular Biology and The Bio21 Molecular Science and Biotechnology Institute The University of Melbourne Parkville Vic. AustraliaDepartment of Biochemistry and Molecular Biology Monash Biomedicine Discovery Institute Monash University Melbourne Vic. AustraliaWellcome Centre for Mitochondrial Research Newcastle University Newcastle upon Tyne UKWellcome Centre for Mitochondrial Research Newcastle University Newcastle upon Tyne UKPathology Department Hospital Sant Joan de Déu CIBERER Barcelona SpainNeuromuscular Unit Neuropaediatrics Department Hospital Sant Joan de Déu CIBERER ‐ ISCIII Barcelona SpainNeuromuscular Unit Neuropaediatrics Department Hospital Sant Joan de Déu CIBERER ‐ ISCIII Barcelona SpainNeuromuscular Unit Neuropaediatrics Department Hospital Sant Joan de Déu CIBERER ‐ ISCIII Barcelona SpainWellcome Centre for Mitochondrial Research Newcastle University Newcastle upon Tyne UKWellcome Centre for Mitochondrial Research Newcastle University Newcastle upon Tyne UKOxford Medical Genetics Laboratories Churchill Hospital Oxford University Hospitals NHS Foundation Trust Oxford UKInstitute of Biotechnology University of Helsinki Helsinki FinlandWellcome Centre for Mitochondrial Research Newcastle University Newcastle upon Tyne UKInstitute for Cell and Molecular Biosciences Newcastle University Institute for Ageing Newcastle University Newcastle upon Tyne UKInstitute of Biotechnology University of Helsinki Helsinki FinlandDepartment of Molecular and Human Genetics Baylor College of Medicine Houston TX USADepartment of Biochemistry and Molecular Biology Monash Biomedicine Discovery Institute Monash University Melbourne Vic. AustraliaWellcome Centre for Mitochondrial Research Newcastle University Newcastle upon Tyne UKWellcome Centre for Mitochondrial Research Newcastle University Newcastle upon Tyne UKWellcome Centre for Mitochondrial Research Newcastle University Newcastle upon Tyne UKAbstract 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.https://doi.org/10.15252/emmm.201809060encephalopathyinsertasemitochondriaOXA1LOXPHOS |
| spellingShingle | Kyle Thompson Nicole Mai Monika Oláhová Filippo Scialó Luke E Formosa David A Stroud Madeleine Garrett Nichola Z Lax Fiona M Robertson Cristina Jou Andres Nascimento Carlos Ortez Cecilia Jimenez‐Mallebrera Steven A Hardy Langping He Garry K Brown Paula Marttinen Robert McFarland Alberto Sanz Brendan J Battersby Penelope E Bonnen Michael T Ryan Zofia MA Chrzanowska‐Lightowlers Robert N Lightowlers Robert W Taylor OXA1L mutations cause mitochondrial encephalopathy and a combined oxidative phosphorylation defect EMBO Molecular Medicine encephalopathy insertase mitochondria OXA1L OXPHOS |
| title | OXA1L mutations cause mitochondrial encephalopathy and a combined oxidative phosphorylation defect |
| title_full | OXA1L mutations cause mitochondrial encephalopathy and a combined oxidative phosphorylation defect |
| title_fullStr | OXA1L mutations cause mitochondrial encephalopathy and a combined oxidative phosphorylation defect |
| title_full_unstemmed | OXA1L mutations cause mitochondrial encephalopathy and a combined oxidative phosphorylation defect |
| title_short | OXA1L mutations cause mitochondrial encephalopathy and a combined oxidative phosphorylation defect |
| title_sort | oxa1l mutations cause mitochondrial encephalopathy and a combined oxidative phosphorylation defect |
| topic | encephalopathy insertase mitochondria OXA1L OXPHOS |
| url | https://doi.org/10.15252/emmm.201809060 |
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