SIRT3 regulates PFKFB3-mediated glycolysis to attenuate cisplatin-induced ototoxicity both in vivo and in vitro.

IF 4.8 2区 医学 Q1 TOXICOLOGY
Wei Tang, Shimin Zong, Peiyu Du, Xuan Yu, Ting Li, Bo Liu, Yu Zhong, Wenyang Lei, Wenting Yu, Hongjun Xiao
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Abstract

Cochlear hair cell death is the primary cause of cisplatin-induced ototoxicity, currently lacking widely applicable clinical methods for effective prevention and treatment. In this study, an in vivo cisplatin-induced ototoxicity model was established by intraperitoneal injection of 12 mg/kg cisplatin. We found that ablation of SIRT3 exacerbates cisplatin-induced hearing loss and cochlear hair cell damage. An in vitro cisplatin-induced ototoxicity model was established using 5 µM cisplatin in cochlear explants and OC-1 cells. We found that the absence of SIRT3 impairs cochlear hair cell glycolytic metabolism, leading to excessive accumulation of ROS and significant reduction in MMP levels, thereby promoting apoptosis. In contrast, overexpression of SIRT3 in OC-1 cells promotes cochlear hair cell survival and reduces cochlear hair cell apoptosis. Inhibition of PFKFB3 reduces glycolytic metabolism in OC-1 cells, and the protective effect conferred by SIRT3 overexpression is lost. In summary, the protective effect of SIRT3 may be mediated by the regulation of PFKFB3-dependent glycolysis and the mitigation of cisplatin-induced excessive ROS accumulation.

SIRT3调节pfkfb3介导的糖酵解,以减轻体内和体外顺铂诱导的耳毒性。
耳蜗毛细胞死亡是顺铂所致耳毒性的主要原因,目前缺乏广泛适用的临床有效预防和治疗方法。本研究通过腹腔注射12 mg/kg顺铂建立体内顺铂致耳毒性模型。我们发现SIRT3消融加重了顺铂诱导的听力损失和耳蜗毛细胞损伤。采用5µM顺铂对人工耳蜗和OC-1细胞建立顺铂诱导的体外耳毒性模型。我们发现SIRT3缺失会损害耳蜗毛细胞糖酵解代谢,导致ROS过度积累,MMP水平显著降低,从而促进细胞凋亡。而OC-1细胞过表达SIRT3可促进耳蜗毛细胞存活,减少耳蜗毛细胞凋亡。抑制PFKFB3降低OC-1细胞的糖酵解代谢,SIRT3过表达的保护作用丧失。综上所述,SIRT3的保护作用可能是通过调节pfkfb3依赖性糖酵解和减轻顺铂诱导的过度ROS积累来介导的。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Archives of Toxicology
Archives of Toxicology 医学-毒理学
CiteScore
11.60
自引率
4.90%
发文量
218
审稿时长
1.5 months
期刊介绍: Archives of Toxicology provides up-to-date information on the latest advances in toxicology. The journal places particular emphasis on studies relating to defined effects of chemicals and mechanisms of toxicity, including toxic activities at the molecular level, in humans and experimental animals. Coverage includes new insights into analysis and toxicokinetics and into forensic toxicology. Review articles of general interest to toxicologists are an additional important feature of the journal.
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