Lu Yu, Bartoszek Ewelina M, Cortada Maurizio, Bodmer Daniel, Levano Huaman Soledad
Department of Biomedicine, University of Basel Hospital, Basel, Switzerland.
Department of Otolaryngology, Head and Neck Surgery, University of Basel Hospital, Basel, Switzerland.
Cell Death Discov. 2024 Oct 21;10(1):445. doi: 10.1038/s41420-024-02215-9.
Preservation of hair cells is critical for maintaining hearing function, as damage to sensory cells potentially leads to irreparable sensorineural hearing loss. Hair cell loss is often associated with inflammation and oxidative stress. One promising class of bioactive peptides is mitochondrial-derived peptides (MDPs), which have already been proven to protect various tissues from cellular stresses and delay aging processes. Humanin (HN) is one of the best-known members of this family, and recently, we have shown its protective effect in hair cells. The synthetic derivate HN S14G (HNG) has a more potent protective effect than natural HN making it a more useful peptide candidate to promote cytoprotection. A less-known MDP is small humanin-like peptide 3 (SHLP3), which has cytoprotective effects similar to HN, but likely acts through different signaling pathways. Therefore, we examined the effect of exogenous HNG and SHLP3 in auditory hair cells and investigated the molecular mechanisms involved. For this purpose, explants of the organ of Corti (OC) were treated with gentamicin in the presence and absence of HNG or SHLP3. Administration of HNG and SHLP3 reduced gentamicin-induced hair cell loss. The protective mechanisms of HNG and SHLP3 in OC explants included, in part, modulation of AKT and AMPKα. In addition, treatment with HNG and SHLP3 reduced gentamicin-induced oxidative stress and inflammatory gene overexpression. Overall, our data show that HNG and SHLP3 protect hair cells from gentamicin-induced toxicity. This offers new perspectives for the development of therapeutic strategies with MDPs against hearing loss.
毛细胞的保存对于维持听力功能至关重要，因为感觉细胞受损可能导致不可修复的感音神经性听力损失。毛细胞损失通常与炎症和氧化应激有关。一类有前景的生物活性肽是线粒体衍生肽（MDPs），其已被证明可保护各种组织免受细胞应激并延缓衰老过程。人胰岛素（HN）是该家族最著名的成员之一，最近，我们已证明其对毛细胞具有保护作用。合成衍生物HN S14G（HNG）比天然HN具有更强的保护作用，使其成为促进细胞保护的更有用的肽候选物。一种不太知名的MDP是小类人胰岛素肽3（SHLP3），其具有与HN相似的细胞保护作用，但可能通过不同的信号通路起作用。因此，我们研究了外源性HNG和SHLP3对听觉毛细胞的影响，并探讨了其中涉及的分子机制。为此，在有和没有HNG或SHLP3的情况下，用庆大霉素处理柯蒂氏器（OC）外植体。给予HNG和SHLP3可减少庆大霉素诱导的毛细胞损失。HNG和SHLP3在OC外植体中的保护机制部分包括对AKT和AMPKα的调节。此外，用HNG和SHLP3处理可减少庆大霉素诱导的氧化应激和炎症基因过表达。总体而言，我们的数据表明HNG和SHLP3可保护毛细胞免受庆大霉素诱导的毒性。这为开发针对听力损失的MDP治疗策略提供了新的视角。
