Department of Cell and Developmental Biology, State University of New York Upstate Medical University, Syracuse, NY 13210, USA.
BioInspired Syracuse: Institute for Material and Living Systems, Syracuse, NY 13244, USA.
Dis Model Mech. 2021 Jul 1;14(7). doi: 10.1242/dmm.048997. Epub 2021 Jul 23.
The vacuolar-type H+-ATPase (V-ATPase) is a multi-subunit proton pump that regulates cellular pH. V-ATPase activity modulates several cellular processes, but cell-type-specific functions remain poorly understood. Patients with mutations in specific V-ATPase subunits can develop sensorineural deafness, but the underlying mechanisms are unclear. Here, we show that V-ATPase mutations disrupt the formation of zebrafish neuromasts, which serve as a model to investigate hearing loss. V-ATPase mutant neuromasts are small and contain pyknotic nuclei that denote dying cells. Molecular markers and live imaging show that loss of V-ATPase induces mechanosensory hair cells in neuromasts, but not neighboring support cells, to undergo caspase-independent necrosis-like cell death. This is the first demonstration that loss of V-ATPase can lead to necrosis-like cell death in a specific cell type in vivo. Mechanistically, loss of V-ATPase reduces mitochondrial membrane potential in hair cells. Modulating the mitochondrial permeability transition pore, which regulates mitochondrial membrane potential, improves hair cell survival. These results have implications for understanding the causes of sensorineural deafness, and more broadly, reveal functions for V-ATPase in promoting survival of a specific cell type in vivo.
液泡型 H+-ATP 酶（V-ATPase）是一种多亚基质子泵，可调节细胞 pH 值。V-ATPase 的活性调节着多种细胞过程，但细胞特异性功能仍知之甚少。具有特定 V-ATPase 亚基突变的患者可能会发生感觉神经性耳聋，但潜在机制尚不清楚。在这里，我们展示了 V-ATPase 突变会破坏斑马鱼毛细胞的形成，而毛细胞可作为研究听力损失的模型。V-ATPase 突变体毛细胞较小，并且含有表示死亡细胞的固缩核。分子标记和活体成像表明，V-ATPase 的缺失会诱导毛细胞发生细胞坏死样细胞死亡，而不是相邻的支持细胞。这是首次证明 V-ATPase 的缺失会导致体内特定细胞类型发生坏死样细胞死亡。从机制上讲，V-ATPase 的缺失会降低毛细胞中的线粒体膜电位。调节线粒体膜电位的线粒体通透性转换孔的调制可改善毛细胞的存活。这些结果对于理解感觉神经性耳聋的原因具有重要意义，并且更广泛地揭示了 V-ATPase 在促进体内特定细胞类型存活方面的功能。
