OXA1L mutations cause mitochondrial encephalopathy and a combined oxidative phosphorylation defect

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. This work describes the first confirmed pathogenic variants in OXA1L in a mitochondrial disease patient with tissue‐specific combined OXPHOS deficiencies. OXA1L was shown to be important for complex IV assembly in human cell lines with targeted depletion of OXA1L and in patient tissues. This work describes the first confirmed pathogenic variants in OXA1L in a mitochondrial disease patient with tissue specific combined OXPHOS deficiencies. OXA1L was shown to be important for complex IV assembly in human cell lines with targeted depletion of OXA1L and in patient tissues.