Department of Otolaryngology Head and Neck Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China; Clinical Center for Hearing Loss, Capital Medical University, Beijing, 100050, China.
Department of Otolaryngology Head and Neck Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China; Clinical Center for Hearing Loss, Capital Medical University, Beijing, 100050, China.
Exp Cell Res. 2022 Sep 15;418(2):113280. doi: 10.1016/j.yexcr.2022.113280. Epub 2022 Jul 11.
Oxidative stress is considered a driving event in the damage to inner hair cell (IHC) synapses. Mitochondrial deacetylase sirtuin 3 (SIRT3) is an important regulator of reactive oxygen species (ROS) production. However, the effect of SIRT3 on IHC synapses remains elusive. In this study, we treated cochlear basilar membrane (CBM) with hydrogen peroxide (HO) to establish an oxidative stress model in vitro. The HO-induced CBM exhibited decreased the number of IHC synapses with low levels of ATP and mitochondrial membrane potential. Additionally, HO-induced CBM showed markedly reduced levels of forkhead box protein O 3a (FOXO3a), superoxide dismutase 2 (SOD2), and isocitrate dehydrogenase 2 (IDH2), thereby increasing ROS generation. SIRT3 overexpression via administrating nicotinamide riboside in the HO-induced CBM protected IHC synapses against oxidative stress and inhibited hair cell apoptosis. We further demonstrated that SIRT3 overexpression led to upregulation of IDH2, and hypoacetylation of several proteins, such as FOXO3a and SOD2, which in turn reduced the levels of ROS and improved mitochondrial function. Collectively, these findings reveal that overexpressing SIRT3 may be a potential therapeutic approach for damaged IHC synapses induced by oxidative stress.
氧化应激被认为是内耳毛细胞（IHC）突触损伤的驱动事件。线粒体去乙酰化酶 SIRT3 是活性氧（ROS）产生的重要调节剂。然而，SIRT3 对 IHC 突触的影响仍不清楚。在这项研究中，我们用过氧化氢（HO）处理耳蜗基底膜（CBM），在体外建立氧化应激模型。HO 诱导的 CBM 显示 IHC 突触数量减少，ATP 和线粒体膜电位水平降低。此外，HO 诱导的 CBM 中叉头框蛋白 O3a（FOXO3a）、超氧化物歧化酶 2（SOD2）和异柠檬酸脱氢酶 2（IDH2）水平明显降低，从而增加 ROS 的产生。通过在 HO 诱导的 CBM 中给予烟酰胺核苷进行 SIRT3 过表达，可保护 IHC 突触免受氧化应激，并抑制毛细胞凋亡。我们进一步证明，SIRT3 过表达导致 IDH2 的上调，以及 FOXO3a 和 SOD2 等几种蛋白质的低乙酰化，从而降低 ROS 水平并改善线粒体功能。总之，这些发现表明，过表达 SIRT3 可能是治疗氧化应激诱导的 IHC 突触损伤的一种潜在治疗方法。
