OXA1L mutations cause mitochondrial encephalopathy and a combined oxidative phosphorylation defect

Area of Science:

• Mitochondrial biology
• Human genetics
• Biochemistry

Background:

• OXA1L is a mitochondrial protein insertase family member.
• In yeast, OXA1 is essential for oxidative phosphorylation complexes IV and V assembly.
• Previous studies suggested human OXA1L (OXA1L) affects only complexes I and V.

Observation:

• A patient with severe encephalopathy, hypotonia, and developmental delay exhibited complex IV deficiency.
• Whole exome sequencing revealed biallelic OXA1L variants segregating with the disease.
• Patient-derived cells showed reduced OXA1L and deficiencies in respiratory chain complexes IV and V.

Findings:

• OXA1L variants were confirmed as pathogenic.
• Depleting OXA1L in human cells and Drosophila melanogaster impaired assembly of complexes I, IV, and V.
• OXA1L co-immunoprecipitated with mtDNA-encoded subunits of complexes I, IV, and V.

Implications:

• OXA1L is essential for the assembly of multiple respiratory chain complexes, including I, IV, and V.
• OXA1L variants are a cause of severe mitochondrial disease.
• This study clarifies the role of OXA1L in mitochondrial respiration and disease pathogenesis.