OXA1L mutations cause mitochondrial encephalopathy and a combined oxidative phosphorylation defect

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 & 5 others Penelope E. Bonnen, Michael T. Ryan, Zofia M.A. Chrzanowska-Lightowlers, Robert N. Lightowlers, Robert W. Taylor

Research output: Contribution to journalArticleResearchpeer-review

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.

Original languageEnglish
Article numbere9060
Number of pages13
JournalEMBO Molecular Medicine
Volume10
Issue number11
DOIs
Publication statusPublished - 1 Nov 2018

Keywords

  • encephalopathy
  • insertase
  • mitochondria
  • OXA1L
  • OXPHOS

Cite this

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 M.A. ; Lightowlers, Robert N. ; Taylor, Robert W. / OXA1L mutations cause mitochondrial encephalopathy and a combined oxidative phosphorylation defect. In: EMBO Molecular Medicine. 2018 ; Vol. 10, No. 11.
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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.",
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author = "Kyle Thompson and Nicole Mai and Monika Ol{\'a}hov{\'a} and Filippo Scial{\'o} and Formosa, {Luke E.} and Stroud, {David A.} and Madeleine Garrett and Lax, {Nichola Z.} and Robertson, {Fiona M.} and Cristina Jou and Andres Nascimento and Carlos Ortez and Cecilia Jimenez-Mallebrera and Hardy, {Steven A.} and Langping He and Brown, {Garry K.} and Paula Marttinen and Robert McFarland and Alberto Sanz and Battersby, {Brendan J.} and Bonnen, {Penelope E.} and Ryan, {Michael T.} and Chrzanowska-Lightowlers, {Zofia M.A.} and Lightowlers, {Robert N.} and Taylor, {Robert W.}",
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Thompson, K, Mai, N, Oláhová, M, Scialó, F, Formosa, LE, Stroud, DA, Garrett, M, Lax, NZ, Robertson, FM, Jou, C, Nascimento, A, Ortez, C, Jimenez-Mallebrera, C, Hardy, SA, He, L, Brown, GK, Marttinen, P, McFarland, R, Sanz, A, Battersby, BJ, Bonnen, PE, Ryan, MT, Chrzanowska-Lightowlers, ZMA, Lightowlers, RN & Taylor, RW 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

OXA1L mutations cause mitochondrial encephalopathy and a combined oxidative phosphorylation defect. / 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 M.A.; Lightowlers, Robert N.; Taylor, Robert W.

In: EMBO Molecular Medicine, Vol. 10, No. 11, e9060, 01.11.2018.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - OXA1L mutations cause mitochondrial encephalopathy and a combined oxidative phosphorylation defect

AU - Thompson, Kyle

AU - Mai, Nicole

AU - Oláhová, Monika

AU - Scialó, Filippo

AU - Formosa, Luke E.

AU - Stroud, David A.

AU - Garrett, Madeleine

AU - Lax, Nichola Z.

AU - Robertson, Fiona M.

AU - Jou, Cristina

AU - Nascimento, Andres

AU - Ortez, Carlos

AU - Jimenez-Mallebrera, Cecilia

AU - Hardy, Steven A.

AU - He, Langping

AU - Brown, Garry K.

AU - Marttinen, Paula

AU - McFarland, Robert

AU - Sanz, Alberto

AU - Battersby, Brendan J.

AU - Bonnen, Penelope E.

AU - Ryan, Michael T.

AU - Chrzanowska-Lightowlers, Zofia M.A.

AU - Lightowlers, Robert N.

AU - Taylor, Robert W.

PY - 2018/11/1

Y1 - 2018/11/1

N2 - 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.

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KW - encephalopathy

KW - insertase

KW - mitochondria

KW - OXA1L

KW - OXPHOS

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DO - 10.15252/emmm.201809060

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JF - EMBO Molecular Medicine

SN - 1757-4676

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