GSDMD-mediated mitochondrial dysfunction in marginal cells: A potential driver of inflammation and stria vascularis damage in CIHL
Abstract
Inflammation is among the known causes of cisplatin-induced hearing loss (CIHL), but its exact pathophysiological mechanisms remain unclear. Herein, we demonstrated that pyroptosis—a recently identified inflammatory type of regulated cell death dependent on gasdermin D (GSDMD)—was activated in the cochleae of cisplatin-treated mice, causing CIHL. Meanwhile, treatment with the GSDMD inhibitor necrosulfonamide alleviated CIHL in these mice. To further examine the role of GSDMD-mediated pyroptosis in CIHL, we conducted experiments in Gsdmd- deficient mice . Gsdmd −/− mice demonstrated significantly lower cisplatin-induced cochlear damage than control mice and appeared to be invulnerable to CIHL. Furthermore, GSDMD-mediated pyroptosis in the stria vascularis (SV), but not in the hair cells (HCs), played a dominant role in CIHL. In marginal cells (MCs) of SV, cisplatin induced caspase-dependent GSDMD cleavage, and the pore-forming N-terminal of GSDMD rapidly localized to the mitochondria, leading to abnormal mitochondrial aggregation and oxidative stress. The consequent mitochondrial dysfunction in MCs might result in the severe progression of inflammation, SV damage, and HC loss. Notably, the pharmacological inhibition of pyroptosis using the FDA-approved drug disulfiram effectively alleviated the symptoms of CIHL. Collectively, these findings offer a broad avenue for inhibiting pyroptosis-induced cisplatin ototoxicity and provide valuable theoretical insights for the clinical management of CIHL.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (20)
Yu Xiao
Xiaohan Zhang
Department of Otolaryngology, Shandong Provincial Hospital, Medical Science and Technology Innovation Center, School of Clinical and Basic Medical Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences
Siwei Guo
Hunan Provincial Key Laboratory of Anti-Resistance Microbial Drugs
Ziyi Liu
New Energy Research Institute, School of Environment and Energy
Xiaoxu Zhao
Fengyue Dong
Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Science, Shandong University
Xiuli Bi
Department of Otolaryngology, Shandong Provincial Hospital, Medical Science and Technology Innovation Center, School of Clinical and Basic Medical Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences
Guodong Hong
Department of Otolaryngology, Shandong Provincial Hospital, Medical Science and Technology Innovation Center, School of Clinical and Basic Medical Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences
Miao Chang
Department of Otolaryngology, Shandong Provincial Hospital, Medical Science and Technology Innovation Center, School of Clinical and Basic Medical Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences
Ruifeng Qiao
Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial Ear, Nose and Throat Hospital, Cheeloo College of Medicine, Shandong University
Shengda Cao
Department of Otorhinolaryngology, Qilu Hospital of Shandong University, National Health Commission Key Laboratory of Otorhinolaryngology, Shandong University
Ying Liu
Ming Xia
Department of Otolaryngology, Shandong Provincial Hospital, Medical Science and Technology Innovation Center, School of Clinical and Basic Medical Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences
Wei Yuan
Jing Zhang
Wen Li
Liya Zhu
State Key Laboratory of Digital Medical Engineering, Department of Otolaryngology Head and Neck Surgery, Zhongda Hospital, School of Life Sciences and Technology, School of Medicine, Advanced Institute for Life and Health, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University
Renjie Chai
Jiangang Gao
Xiaolong Fu