Hawkey-Noble Alexia, Tobin Cameron, Ameen Muhammad T, Osmond Liam, Gill Colby, Bottaro Christina S, Young Terry-Lynn, French Curtis R
Division of Biomedical Sciences, Faculty of Medicine, Memorial University of Newfoundland, St John's NL A1B 3V6, Canada.
Department of Chemistry, Faculty of Science, Memorial University of Newfoundland, St John's NL A1C 5S7, Canada.
J Cell Sci. 2025 May 15;138(10). doi: 10.1242/jcs.263657. Epub 2025 May 22.
The atp11a gene encodes a phospholipid flippase protein required to flip phosphatidylserine (PS) and phosphatidylethanolamine (PE) from the outer leaflet of the cytoplasmic membrane to the inner leaflet. Mutations in ATP11A have been described in individuals with sensorineural hearing loss and neurological deterioration; however, little is known regarding the mechanism by which loss of atp11a results in such phenotypes. To this end, we created loss-of-function atp11a mutant zebrafish to characterize potential disease states. We demonstrate that mutant atp11a zebrafish display a reduced number of stereocilia in the larval ear and a reduced number of hair cells in some sensory neuromasts, indicating that these fish represent an ideal model for studying atp11a-attributable hearing loss. In addition, atp11a mutant zebrafish raised in a standard light cycle have reduced photoreceptor outer segments, the severity of which is lessened when mutant larvae are raised in the dark. Photoreceptors that do remain in homozygous atp11a mutants undergo mitochondrial fission and produce an increased number of mitochondria, suggesting that defects in energy homeostasis may contribute to or result from outer segment degradation.
atp11a基因编码一种磷脂翻转酶蛋白，该蛋白可将磷脂酰丝氨酸（PS）和磷脂酰乙醇胺（PE）从细胞质膜的外小叶翻转至内小叶。ATP11A的突变已在患有感音神经性听力损失和神经功能恶化的个体中被描述；然而，关于atp11a缺失导致这些表型的机制知之甚少。为此，我们构建了功能缺失的atp11a突变斑马鱼以表征潜在的疾病状态。我们证明，突变的atp11a斑马鱼幼虫耳部的静纤毛数量减少，一些感觉神经丘中的毛细胞数量也减少，这表明这些鱼是研究atp11a所致听力损失的理想模型。此外，在标准光照周期下饲养的atp11a突变斑马鱼的光感受器外段减少，而当突变幼虫在黑暗中饲养时，这种情况的严重程度会减轻。纯合atp11a突变体中残留的光感受器会发生线粒体裂变并产生更多的线粒体，这表明能量稳态缺陷可能导致外段降解或由外段降解所致。
