Oxa1l, the human homologue of the yeast Oxa1 protein, is a member of the evolutionarily conserved Oxa1/Alb3/YidC protein family. It is an integral mitochondrial inner-membrane protein essential for the cotranslational membrane insertion of mitochondrially-encoded proteins and for the biogenesis of multiple respiratory chain complexes [1,2,4]. It is involved in mitochondrial oxidative phosphorylation and protein transport across membranes, playing a crucial role in maintaining mitochondrial function [3]. Genetic models can be used to study its functions in vivo.

Mutations in Oxa1L in a patient led to severe encephalopathy, hypotonia, and developmental delay, along with complex IV deficiency in skeletal muscle. Targeted depletion of Oxa1L in human cells or Drosophila melanogaster also caused defects in the assembly of complexes I, IV, and V, verifying its pathogenicity and its requirement for the assembly of multiple respiratory chain complexes [2]. In HEK293 cells, stable short hairpin (sh)RNA-mediated knockdown of Oxa1l resulted in decreased steady-state levels and ATP hydrolytic activity of the F1Fo-ATP synthase and moderately reduced levels and activity of NADH:ubiquinone oxidoreductase (complex I) [4].

In conclusion, Oxa1l is vital for the biogenesis of respiratory chain complexes and mitochondrial function. Studies using gene-knockout or knockdown models in humans, Drosophila, and cell lines have revealed its key role in diseases such as mitochondrial encephalopathy, highlighting its importance in understanding the mechanisms of these diseases and potentially providing new insights for treatment strategies.

References:

1. Itoh, Yuzuru, Andréll, Juni, Choi, Austin, Battersby, Brendan J, Amunts, Alexey. . Mechanism of membrane-tethered mitochondrial protein synthesis. In Science (New York, N.Y.), 371, 846-849. doi:10.1126/science.abe0763. https://pubmed.ncbi.nlm.nih.gov/33602856/

2. Thompson, Kyle, Mai, Nicole, Oláhová, Monika, Lightowlers, Robert N, Taylor, Robert W. . OXA1L mutations cause mitochondrial encephalopathy and a combined oxidative phosphorylation defect. In EMBO molecular medicine, 10, . doi:10.15252/emmm.201809060. https://pubmed.ncbi.nlm.nih.gov/30201738/

3. Pires, Anaque de Oliveira, Queiroz, Gerson de Almeida, de Jesus Silva, Milca, Barreto, Maurício L, Figueiredo, Camila Alexandrina. 2018. Polymorphisms in the DAD1 and OXA1L genes are associated with asthma and atopy in a South American population. In Molecular immunology, 101, 294-302. doi:10.1016/j.molimm.2018.07.014. https://pubmed.ncbi.nlm.nih.gov/30032071/

4. Stiburek, Lukas, Fornuskova, Daniela, Wenchich, Laszlo, Hansikova, Hana, Zeman, Jiri. 2007. Knockdown of human Oxa1l impairs the biogenesis of F1Fo-ATP synthase and NADH:ubiquinone oxidoreductase. In Journal of molecular biology, 374, 506-16. doi:. https://pubmed.ncbi.nlm.nih.gov/17936786/