Among older people, age-related hearing loss is the most common sensory disturbance and is characterized by progressive loss of high-frequency hearing (Slade et al., 2020). AHL, which is considered a multifactorial disorder, is thought to have underlying risk factors. In recent studies, it has been found that age-related hearing loss is associated with cognitive decline and Alzheimer's disease, leading to loneliness and depression, as well as a reduction in well-being (Jayakody et al., 2018; Lin et al., 2013; Rutherford et al., 2018; Uchida et al., 2019). Additionally, AHL is associated not only with degeneration of cochlear hair cells and spiral ganglion neurons but also with changes in central auditory pathways (Bowl and Dawson, 2019; Ohlemiller, 2004; Schuknecht and Gacek, 1993). However, the effectiveness of clinical treatments for AHL is extraordinarily limited. Therefore, it is critical to find efficient interventions to ameliorate hearing loss in elderly individuals.

KCNMA1 is the gene that produces the pore-forming α-subunit of the large conductance calcium-activated potassium channel (BK channel) (Bailey et al., 2019; Dworetzky et al., 1994). BK channels are mainly responsible for inciting K+ efflux in different cells, especially in brain and muscle cells (Contet et al., 2016; Tricarico and Mele, 2017). Several previous studies have reported that the BK channel plays a pleiotropic role in many human diseases, such as autism, hypertension, cardiovascular dysfunction and hearing loss (Kurt et al., 2012; Laumonnier et al., 2006). In the mouse inner ear, significant hearing loss due to outer hair cell (OHC) degeneration was observed when KCNMA1 was knocked out (R€uttiger et al., 2004). According to our previous research, BK channels are located in the hair cells, the spiral ganglion and the stria vascularis (Pan et al., 2016). The expression of KCNMA1 was also shown to decrease with aging in the C57BL/6 J cochlea. Despite these findings, the mechanism by which KCNMA1 is decreased by the aging process in auditory hair cells is still unknown.

Ferroptosis, a new type of iron-dependent programmed cell death, is mainly characterized by decreased mitochondrial cristae and ruptured mitochondrial membranes (Dixon et al., 2012; Xie et al., 2016; Yu et al., 2017). In addition, this process is usually accompanied by the accumulation of reactive oxygen species (ROS) and lipid peroxidation (Li et al., 2020). Ferroptosis is classically regulated by glutathione peroxidase 4 (GPX4) (Seibt et al., 2019, Zheng et al., 2020), but its specific regulatory mechanism in various diseases needs further study. There is evidence that ferroptosis plays a crucial role in the development of many diseases, particularly hearing loss (Chen et al., 2020, He et al., 2022, Yan et al., 2022). In vitro, neurodegeneration of the auditory cortex can be partially reversed by reducing ferroptosis (Chen et al., 2020). However, ferroptosis is a complex biological process affected by the function of mitochondria. The most significant features of ferroptosis are changes in mitochondrial morphology, including mitochondrial shrinkage with increased membrane density (Dixon et al., 2012). MitoTEMPO, a mitochondria-targeted antioxidant, significantly inhibited the ferroptosis program induced by DOX in murine hearts (Fang et al., 2019). This study provides strong evidence of a link between mitochondria and ferroptosis.

BK channels are usually expressed in the plasma membrane of muscle and neuronal cells. Interestingly, BK channel activity has been found only in the mitochondria of cardiomyocytes and brain cells (Balderas et al., 2015, Shi et al., 2007, Xu et al., 2002). The influence of mitochondrial BK channels in mitochondrial biology and disease is critical. Furthermore, there was evidence that nonfunctional BK channel mutations caused the death of cerebellar neurons by damaging mitochondrial function, indicating that KCNMA1 might be associated with cell death by regulating mitochondrial function (Du et al., 2020, Li and Gao, 2016, Singh et al., 2013). Based on these evidence, we hypothesized that KCNMA1 could influence ferroptosis by affecting mitochondrial function, thus affecting the auditory hair cell senescence.

As mentioned above, the aim of this study was to explore the role played by KCNMA1 in the aging process of cochlear hair cells. We sought to elucidate the mechanism underlying this phenomenon and its regulation in order to better understand this process. These results provide new insights regarding potential treatments for age-related hearing loss.