Huanyu Mao1,2 · Wenli Ni1,2 · Lupeng Ma3 · Xiang Li1,2 · Yanping Zhang1,2 · Yuzheng Zhao5 · Wenyan Li1,2,4 · Huawei Li1,2,4 · Yan Chen1,21 ENT Institute and Otorhinolaryngology Department of Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200031, China
2 NHC Key Laboratory of Hearing Medicine (Fudan University), Shanghai 200031, China
3 Molecular Medicine Institute, Zhejiang Chinese Medical University, Hangzhou 310053, China
4 The Institutes of Brain Science and the Collaborative Innovation Center for Brain Science, Fudan University, Shanghai 200032, China
5 Optogenetics & Synthetic Biology Interdisciplinary Research Center, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
Abstract
Cochlear hair cell (HC) damage is a primary cause of sensorineural hearing loss. In this study, we performed metabolomic profiling of cochlear sensory epithelium following neomycin-induced HC injury and identified elevated arginine metabolism as a key metabolic characteristic of damaged HCs. Using a highly sensitive and specific biosensor, we confirmed that injury induced an increase in arginine levels within cochlear HCs. By manipulating the levels of arginine and its downstream metabolites, we discovered that unmetabolized arginine exerts a strong protective effect on cochlear HCs, independent of its downstream metabolites, such as nitric oxide. Furthermore, integrated metabolomic and transcriptomic analyses revealed that arginine plays a critical role in reprogramming phospholipid metabolism. Arginine supplementation enhanced membrane phospholipid saturation through the Lands cycle and de novo lipogenesis, and protected HCs from phospholipid peroxidation-induced membrane damage and subsequent cell death. Notably, arginine supplementation protected hearing from both noise- and aminoglycoside-induced injury in mice. These findings underscore the role of unmetabolized arginine in modulating phospholipid metabolism and preventing membrane damage in cochlear HCs, highlighting that targeting phospholipid metabolism is an effective hearing protection strategy.
Keywords
Sensorineural hearing loss; Hair cell; Membrane lipid bilayer; Oxidative stress; Phospholipid remodeling
