title: NLRX1 accelerates cisplatin-induced ototoxity in HEI-OC1 cells via promoting generation of ROS and activation of JNK signaling pathway.
abstract: Nucleotide-binding domain and leucine-rich-repeat-containing family member X1 (NLRX1), located in mitochondria, can recognize cytoplasmic pattern recognition receptors and is tightly related to reactive oxygen species (ROS) production, mitochondrial function, apoptosis and inflammation. The present study was designed to explore whether NLRX1 expresses in HEI-OC1 cells and, if so, to investigate the possible correlations between NLRX1 and cisplatin-induced ototoxity in vitro. Here, we report that NLRX1 was specifically localized to mitochondria in the cytoplasm of HEI-OC1 cells and its expression was increased concurrent with the increase of ROS production and occurrence of apoptosis in HEI-OC1 cells in response to cisplatin stimulus. NLRX1 overexpression led to a higher apoptosis in HEI-OC1 cells treated with cisplatin, whereas, NLRX silencing decreased cisplatin induced apoptosis. Mechanistic studies showed that NLRX1 activated mitochondrial apoptosis pathway as well as promoted ROS generation and JNK activation. Either inhibition of ROS generation or JNK signaling significantly prevented NLRX1-mediated mitochondrial apoptosis in HEI-OC1cells. In addition, NLRX1 expression was confirmed in cochlear explants. The findings from this work reveal that NLRX1 sensitizes HEI-OC1 cells to cisplatin-induced apoptosis via activation of ROS/JNK signaling pathway, suggesting that NLRX1 acts as an important regulator of the cisplatin-elicited ototoxity.
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, 250021, P.R. China.|Department of Pathology and Pathophysiology, Shandong University, Cheeloo Healthy Science Center, Jinan, 250012, P.R. China.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Yin
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, 250021, P.R. China.|Shandong Provincial Key Laboratory of Otology, Jinan, 250021, P.R. China.
authors.forename: Gaoying
authors.initials: G
authors.lastname: Sun
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, 250021, P.R. China.|Department of Pathology and Pathophysiology, Shandong University, Cheeloo Healthy Science Center, Jinan, 250012, P.R. China.
authors.forename: Qianqian
authors.initials: Q
authors.lastname: Yang
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, 250021, P.R. China.|Department of Pathology and Pathophysiology, Shandong University, Cheeloo Healthy Science Center, Jinan, 250012, P.R. China.
authors.forename: Chen
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, 250021, P.R. China.|Department of Pathology and Pathophysiology, Shandong University, Cheeloo Healthy Science Center, Jinan, 250012, P.R. China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Qi
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, 250021, P.R. China.|Shandong Provincial Key Laboratory of Otology, Jinan, 250021, P.R. China.
authors.forename: Haibo
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, 250021, P.R. China.|Department of Pathology and Pathophysiology, Shandong University, Cheeloo Healthy Science Center, Jinan, 250012, P.R. China.|Shandong Provincial Key Laboratory of Otology, Jinan, 250021, P.R. China.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Li
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D003051:Cochlea / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression; D006198:Hair Cells, Auditory / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D024101:Mitochondrial Proteins; C555655:NLRX1 protein, mouse; D017382:Reactive Oxygen Species; D002945:Cisplatin