ROS-Induced Oxidative Damage and Mitochondrial Dysfunction Mediated by Inhibition of SIRT3 in Cultured Cochlear Cells.
ROS-Induced Oxidative Damage and Mitochondrial Dysfunction Mediated by Inhibition of SIRT3 in Cultured Cochlear Cells.
复制标题
ros诱导耳蜗细胞氧化损伤和线粒体功能障碍抑制SIRT3。
DOI：
10.1155/2022/5567174
复制
发表时间：
2022
影响因子：
3.1
通讯作者：
Gong S
中科院分区：
文献类型：
--
作者：
Zhang L;Du Z;He L;Liang W;Liu K;Gong S
感音神经性听力损失（SNHL）是世界范围内最常见的残疾原因之一。已有证据表明，活性氧（reactive oxygen species，ROS）在SNHL的发生发展中起重要作用，但其机制尚不清楚。我们培养解剖的Corti器官在培养基中含有不同浓度（0，0.25，0.5，0.75，1，和1.25 mM）的过氧化氢（H2 O2），并建立了一个四浓度模型0，0.5，0.75，和1 mM的研究不同程度的损害。我们研究了ROS诱导的线粒体损伤和sirtuin 3（SIRT 3）的作用。结果表明，H_2O_2浓度依赖性地减少了海马带状突触和毛细胞的数量。外毛细胞（OHCs）和内毛细胞（IHCs）开始丢失，并分别在0.75 mM和1 mM H2 O2下观察到毛细胞（HC）凋亡的激活。与对照组相比，H2 O2处理组的ROS积累显著增加，线粒体膜电位（MMP）降低。此外，SIRT 3，FOXO 3A和SOD 2蛋白的表达下降，除了SIRT 3在0和0.75 mM H2 O2之间的初始升高。施用选择性SIRT 3抑制剂3-（1H-1，2，3-三唑-4-基）吡啶导致对耳蜗的损伤增加，包括带状突触和毛细胞的损失、毛细胞的凋亡、更多的ROS产生和线粒体膜电位降低。总之，我们的研究结果强调了ROS诱导的线粒体氧化损伤驱动毛细胞变性和凋亡。此外，SIRT 3对于保护线粒体功能和保护耳蜗免受氧化损伤至关重要，并且可能代表SNHL的可能治疗靶点。
Sensorineural hearing loss (SNHL) is one of the most common causes of disability worldwide. Previous evidence suggests that reactive oxygen species (ROS) may play an important role in the occurrence and development of SNHL, while its mechanism remains unclear. We cultured dissected organs of Corti in medium containing different concentrations (0, 0.25, 0.5, 0.75, 1, and 1.25 mM) of hydrogen peroxide (H2O2) and established a four-concentration model of 0, 0.5, 0.75, and 1 mM to study different degrees of damage. We examined ROS-induced mitochondrial damage and the role of sirtuin 3 (SIRT3). Our results revealed that the number of ribbon synapses and hair cells appeared significantly concentration-dependent decrease with exposure to H2O2. Outer hair cells (OHCs) and inner hair cells (IHCs) began to be lost, and activation of apoptosis of hair cells (HCs) was observed at 0.75 mM and 1 mM H2O2, respectively. In contrast with the control group, the accumulation of ROS was significantly higher, and the mitochondrial membrane potential (MMP) was lower in the H2O2-treated groups. Furthermore, the expression of SIRT3, FOXO3A, and SOD2 proteins declined, except for an initial elevation of SIRT3 between 0 and 0.75 mM H2O2. Administration of the selective SIRT3 inhibitor 3-(1H-1,2,3-triazol-4-yl) pyridine resulted in increased damage to the cochlea, including loss of ribbon synapses and hair cells, apoptosis of hair cells, more production of ROS, and reduced mitochondrial membrane potential. Thoroughly, our results highlight that ROS-induced mitochondrial oxidative damage drives hair cell degeneration and apoptosis. Furthermore, SIRT3 is crucial for preserving mitochondrial function and protecting the cochlea from oxidative damage and may represent a possible therapeutic target for SNHL.