Wu Yan, Huang Yu-Yu, Wang Lu-Yao, Yang Yan, Cui Fei-Lun, Li Shu-Na
Department of Otorhinolaryngology-Head and Neck Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Shanghai Jiaotong University School of Medicine Ear Institute, Shanghai, China.
Front Pharmacol. 2024 Aug 13;15:1430162. doi: 10.3389/fphar.2024.1430162. eCollection 2024.
Methyltransferase-like 3 (METTL3), a component of the N6-methyladenosine (m6A) methyltransferase family, exhibits significant expression in HEI-OC1 cells and cochlear explants. Aminoglycoside antibiotics, known for their ototoxic potential, frequently induce irreversible auditory damage in hair cells, predominantly through oxidative stress mechanisms. However, the specific role of METTL3 in kanamycin-induced hair cell loss remains unclear.
This study aims to elucidate the mechanisms by which METTL3 contributes to kanamycin-induced ototoxicity.
experiments demonstrated a notable reduction in METTL3 expression within cochlear explants following kanamycin administration, concomitant with the formation of stress granules (SGs). Similarly, a 24-hour kanamycin treatment led to decreased METTL3 expression and induced SG formation both in HEI-OC1 cells and neonatal cochlear explants, corroborating the observations. Lentivirus-mediated transfection was employed to overexpress and knockdown METTL3 in HEI-OC1 cells. Knockdown of METTL3 resulted in increased reactive oxygen species (ROS) levels and apoptosis induced by kanamycin, while concurrently reducing SG formation. Conversely, overexpression of METTL3 attenuated ROS generation, decreased apoptosis rates, and promoted SG formation induced by kanamycin. Therefore, METTL3-mediated SG formation presents a promising target for mitigating kanamycin-induced ROS generation and the rate of apoptosis.
This finding indicates that METTL3-mediated SG formation holds potential in mitigating kanamycin-induced impairments in cochlear hair cells by reducing ROS formation and apoptosis rates.
甲基转移酶样3（METTL3）是N6-甲基腺苷（m6A）甲基转移酶家族的一个组成部分，在HEI-OC1细胞和耳蜗外植体中表达显著。氨基糖苷类抗生素以其耳毒性而闻名，经常在毛细胞中诱导不可逆的听觉损伤，主要通过氧化应激机制。然而，METTL3在卡那霉素诱导的毛细胞损失中的具体作用仍不清楚。
本研究旨在阐明METTL3导致卡那霉素诱导的耳毒性的机制。
实验表明，给予卡那霉素后，耳蜗外植体中METTL3表达显著降低，同时伴有应激颗粒（SGs）的形成。同样，24小时的卡那霉素处理导致HEI-OC1细胞和新生耳蜗外植体中METTL3表达降低并诱导SG形成，证实了这些观察结果。采用慢病毒介导的转染在HEI-OC1细胞中过表达和敲低METTL3。敲低METTL3导致卡那霉素诱导的活性氧（ROS）水平升高和细胞凋亡增加，同时减少SG形成。相反，METTL3的过表达减弱了ROS的产生，降低了凋亡率，并促进了卡那霉素诱导的SG形成。因此，METTL3介导的SG形成是减轻卡那霉素诱导的ROS产生和凋亡率的一个有前景的靶点。
这一发现表明，METTL3介导的SG形成有可能通过降低ROS形成和凋亡率来减轻卡那霉素诱导的耳蜗毛细胞损伤。
