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 muut Penelope E Bonnen, Michael T Ryan, Zofia Ma Chrzanowska-Lightowlers, Robert N Lightowlers, Robert W Taylor

Tutkimustuotos: ArtikkelijulkaisuArtikkeliTieteellinenvertaisarvioitu

Kuvaus

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.
Alkuperäiskielienglanti
Artikkelie9060
LehtiEMBO molecular medicine
Vuosikerta10
Numero11
Sivumäärä13
ISSN1757-4676
DOI - pysyväislinkit
TilaJulkaistu - 1 marraskuuta 2018
OKM-julkaisutyyppiA1 Alkuperäisartikkeli tieteellisessä aikakauslehdessä, vertaisarvioitu

Tieteenalat

  • 1182 Biokemia, solu- ja molekyylibiologia

Lainaa tätä

Thompson, K., Mai, N., Oláhová, M., Scialó, F., Formosa, L. E., Stroud, D. A., ... Taylor, R. W. (2018). OXA1L mutations cause mitochondrial encephalopathy and a combined oxidative phosphorylation defect. EMBO molecular medicine, 10(11), [e9060]. https://doi.org/10.15252/emmm.201809060
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. / OXA1L mutations cause mitochondrial encephalopathy and a combined oxidative phosphorylation defect. Julkaisussa: EMBO molecular medicine. 2018 ; Vuosikerta 10, Nro 11.
@article{ebabd392d0944e42b6ccd4086e5d3beb,
title = "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 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.",
keywords = "OXPHOS, OXA1L, encephalopathy, insertase, mitochondria, 1182 Biochemistry, cell and molecular biology",
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 Ma} and Lightowlers, {Robert N} and Taylor, {Robert W}",
year = "2018",
month = "11",
day = "1",
doi = "10.15252/emmm.201809060",
language = "English",
volume = "10",
journal = "EMBO molecular medicine",
issn = "1757-4676",
publisher = "Wiley",
number = "11",

}

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, ZM, Lightowlers, RN & Taylor, RW 2018, 'OXA1L mutations cause mitochondrial encephalopathy and a combined oxidative phosphorylation defect', EMBO molecular medicine, Vuosikerta 10, Nro 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 Ma; Lightowlers, Robert N; Taylor, Robert W.

julkaisussa: EMBO molecular medicine, Vuosikerta 10, Nro 11, e9060, 01.11.2018.

Tutkimustuotos: ArtikkelijulkaisuArtikkeliTieteellinenvertaisarvioitu

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 Ma

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.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.

AB - 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.

KW - OXPHOS

KW - OXA1L

KW - encephalopathy

KW - insertase

KW - mitochondria

KW - 1182 Biochemistry, cell and molecular biology

U2 - 10.15252/emmm.201809060

DO - 10.15252/emmm.201809060

M3 - Article

VL - 10

JO - EMBO molecular medicine

JF - EMBO molecular medicine

SN - 1757-4676

IS - 11

M1 - e9060

ER -