TRPV4 disrupts mitochondrial transport and causes axonal degeneration via a CaMKII-dependent elevation of intracellular Ca2+

作者：Brian M. Woolums, Brett A. McCray, Hyun Sung, Masashi Tabuchi, Jeremy M. Sullivan, Kendra Takle Ruppell, Yunpeng Yang, Catherine Mamah, William H. Aisenberg, Pamela C. Saavedra-Rivera, Bryan S. Larin, Alexander R. Lau, Douglas N. Robinson, Yang Xiang, Mark N. Wu, Charlotte J. Sumner, Thomas E. Lloyd · 发表于：Nature Communications · 年份：2020 · DOI：10.1038/s41467-020-16411-5 · 被引用次数：71 · 研究领域：Ion Channels and Receptors、Coenzyme Q10 studies and effects、Plant Stress Responses and Tolerance

Abstract The cation channel transient receptor potential vanilloid 4 (TRPV4) is one of the few identified ion channels that can directly cause inherited neurodegeneration syndromes, but the molecular mechanisms are unknown. Here, we show that in vivo expression of a neuropathy-causing TRPV4 mutant (TRPV4 R269C ) causes dose-dependent neuronal dysfunction and axonal degeneration, which are rescued by genetic or pharmacological blockade of TRPV4 channel activity. TRPV4 R269C triggers increased intracellular Ca 2+ through a Ca 2+ /calmodulin-dependent protein kinase II (CaMKII)-mediated mechanism, and CaMKII inhibition prevents both increased intracellular Ca 2+ and neurotoxicity in Drosophila and cultured primary mouse neurons. Importantly, TRPV4 activity impairs axonal mitochondrial transport, and TRPV4-mediated neurotoxicity is modulated by the Ca 2+ -binding mitochondrial GTPase Miro. Our data highlight an integral role for CaMKII in neuronal TRPV4-associated Ca 2+ responses, the importance of tightly regulated Ca 2+ dynamics for mitochondrial axonal transport, and the therapeutic promise of TRPV4 antagonists for patients with TRPV4-related neurodegenerative diseases.