Open AccessOXA 1L mutations cause mitochondrial encephalopathy and a combined oxidative phosphorylation defect
Author(s) -
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,
JimenezMallebrera Cecilia,
Hardy Steven A,
He Langping,
Brown Garry K,
Marttinen Paula,
McFarland Robert,
Sanz Alberto,
Battersby Brendan J,
Bonnen Penelope E,
Ryan Michael T,
ChrzanowskaLightowlers Zofia MA,
Lightowlers Robert N,
Taylor Robert W
Publication year - 2018
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201809060
Subject(s) - oxidative phosphorylation , phosphorylation , mutation , mitochondrion , chemistry , genetics , microbiology and biotechnology , biology , biochemistry , gene
OXA 1, 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 OXA 1 ( OXA 1L) 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 OXA 1L variants (c.500_507dup, p.(Ser170Glnfs*18) and c.620G>T, p.(Cys207Phe)) that segregated with disease. Patient muscle and fibroblasts showed decreased OXA 1L and subunits of complexes IV and V. Crucially, expression of wild‐type human OXA 1L in patient fibroblasts rescued the complex IV and V defects. Targeted depletion of OXA 1L in human cells or Drosophila melanogaster caused defects in the assembly of complexes I, IV and V, consistent with patient data. Immunoprecipitation of OXA 1L revealed the enrichment of mt DNA ‐encoded subunits of complexes I, IV and V. Our data verify the pathogenicity of these OXA 1L variants and demonstrate that OXA 1L is required for the assembly of multiple respiratory chain complexes.