Atp5po, encoding the oligomycin sensitivity conferring protein, is a subunit of mitochondrial complex V. Mitochondrial complex V is crucial for oxidative phosphorylation, catalyzing ATP generation, thus playing a vital role in energy metabolism [2]. Genetic models like zebrafish are valuable for studying Atp5po due to its conserved function across species.

In zebrafish, overexpression of Atp5po led to a significant reduction of enteric nervous system (ENS) cells, along with impaired neuronal differentiation and reduced mitochondrial ATP production. Epistasis was observed between ATP5PO and ret, a key gene in Hirschsprung disease (HSCR). This indicates that ATP5PO may be responsible for the increased HSCR risk in Down Syndrome (DS) patients, especially when RET variants are present [1]. In two unrelated families, a homozygous splice variant in ATP5PO disrupted mitochondrial complex V function, causing Leigh syndrome, with affected individuals showing severe multi-systemic disorders [2]. An intronic splice-disrupting alteration in compound heterozygosity with a nonsense variant in ATP5PO was found in a patient with variable neurologic phenotypes associated with mitochondrial ATP synthase mutations [3].

In summary, Atp5po is essential for mitochondrial complex V function and energy metabolism. Studies in zebrafish and human families with genetic variants in Atp5po have revealed its role in ENS development, and its association with HSCR in DS, as well as Leigh syndrome and variable neurologic phenotypes. These findings enhance our understanding of the biological functions of Atp5po and its implications in related diseases.

References:

1. Kuil, L E, Chauhan, R K, de Graaf, B M, Brosens, E, Alves, M M. 2023. ATP5PO levels regulate enteric nervous system development in zebrafish, linking Hirschsprung disease to Down Syndrome. In Biochimica et biophysica acta. Molecular basis of disease, 1870, 166991. doi:10.1016/j.bbadis.2023.166991. https://pubmed.ncbi.nlm.nih.gov/38128843/

2. Ganapathi, Mythily, Friocourt, Gaelle, Gueguen, Naig, Le Marechal, Cedric, Chung, Wendy K. 2022. A homozygous splice variant in ATP5PO, disrupts mitochondrial complex V function and causes Leigh syndrome in two unrelated families. In Journal of inherited metabolic disease, 45, 996-1012. doi:10.1002/jimd.12526. https://pubmed.ncbi.nlm.nih.gov/35621276/

3. Zech, Michael, Kopajtich, Robert, Steinbrücker, Katja, Winkelmann, Juliane, Prokisch, Holger. 2022. Variants in Mitochondrial ATP Synthase Cause Variable Neurologic Phenotypes. In Annals of neurology, 91, 225-237. doi:10.1002/ana.26293. https://pubmed.ncbi.nlm.nih.gov/34954817/