Suzuki Yuna, Hayashi Ken, Goto Fumiyuki, Nomura Yasuyuki, Fujimoto Chisato, Makishima Makoto
Division of Biochemistry, Department of Biomedical Sciences, Nihon University School of Medicine, Tokyo, Japan.
Department of Otolaryngology, Sakura Koedo Clinic, Saitama, Japan.
Cell Death Discov. 2024 Aug 28;10(1):382. doi: 10.1038/s41420-024-02139-4.
Age-related hearing loss (ARHL) is one of the most prevalent types of sensory decline in a superaging society. Although various studies have focused on the effect of oxidative stress on the inner ear as an inducer of ARHL, there are no effective preventive approaches for ARHL. Recent studies have suggested that oxidative stress-induced DNA damage responses (oxidative DDRs) drive cochlear cell senescence and contribute to accelerated ARHL, and autophagy could function as a defense mechanism against cellular senescence in auditory cells. However, the underlying mechanism remains unclear. Sodium arsenite (NaAsO) is a unique oxidative stress inducer associated with reactive oxygen species (ROS) that causes high-tone hearing loss similar to ARHL. Transcription factor EB (TFEB) functions as a master regulator of the autophagy‒lysosome pathway (ALP), which is a potential target during aging and the pathogenesis of various age-related diseases. Here, we focused on the function of TFEB and the impact of intracellular ROS as a potential target for ARHL treatment in a NaAsO-induced auditory premature senescence model. Our results suggested that short exposure to NaAsO leads to DNA damage, lysosomal damage and mitochondrial damage in auditory cells, triggering temporary signals for TFEB transport into the nucleus and, as a result, causing insufficient autophagic flux and declines in lysosomal function and biogenesis and mitochondrial quality. Then, intracellular ROS derived from damaged mitochondria play a role as a second messenger to induce premature senescence in auditory cells. These findings suggest that TFEB activation via transport into the nucleus contributes to anti-senescence activity in auditory cells and represents a new therapeutic target for ARHL. We have revealed the potential function of TFEB as a master regulator of the induction of oxidative stress-induced premature senescence and the senescence-associated secretion phenotype (SASP) in auditory cells, which regulates ALP and controls mitochondrial quality through ROS production.
年龄相关性听力损失（ARHL）是超老龄化社会中最普遍的感觉功能衰退类型之一。尽管各种研究都聚焦于氧化应激作为ARHL诱导因素对内耳的影响，但目前尚无针对ARHL的有效预防方法。最近的研究表明，氧化应激诱导的DNA损伤反应（氧化DDRs）驱动耳蜗细胞衰老并导致ARHL加速，而自噬可能作为听觉细胞中对抗细胞衰老的防御机制。然而，其潜在机制仍不清楚。亚砷酸钠（NaAsO）是一种与活性氧（ROS）相关的独特氧化应激诱导剂，可导致类似于ARHL的高频听力损失。转录因子EB（TFEB）作为自噬-溶酶体途径（ALP）的主要调节因子，是衰老及各种年龄相关疾病发病过程中的一个潜在靶点。在此，我们在NaAsO诱导的听觉早衰模型中，聚焦于TFEB的功能以及细胞内ROS作为ARHL治疗潜在靶点的影响。我们的结果表明，短期暴露于NaAsO会导致听觉细胞中的DNA损伤、溶酶体损伤和线粒体损伤，触发TFEB转运至细胞核的临时信号，从而导致自噬通量不足、溶酶体功能和生物合成以及线粒体质量下降。然后，受损线粒体产生的细胞内ROS作为第二信使，诱导听觉细胞早衰。这些发现表明，TFEB通过转运至细胞核而被激活有助于听觉细胞的抗衰老活性，代表了ARHL的一个新治疗靶点。我们揭示了TFEB作为氧化应激诱导的早衰和听觉细胞衰老相关分泌表型（SASP）诱导的主要调节因子的潜在功能，其通过ROS产生调节ALP并控制线粒体质量。
