Hearing loss has emerged as a major public health concern with significant social and economic implications. According to recent estimates, over 1.5 billion people globally experience hearing loss, of whom 430 million (5.5% of the global population) suffer from moderate to severe hearing loss (Haile et al., 2021). The most prevalent type of hearing loss is sensorineural hearing loss (SNHL), which is typically attributed to degenerative changes in sensory hair cells, their synapses, and/or spiral ganglion neurons (SGNs) in the cochlea. Because mammalian hair cells and SGNs lack regenerative capacity, their death is irreversible, leading to permanent hearing loss. The most common form of SNHL is age-related hearing loss (ARHL), also known as presbycusis, which is the leading cause of global years lived with disability (YLD) for adults over 70 (Haile et al., 2021). Due to the increasing average life expectancy of the world population, the prevalence of ARHL is expected to grow substantially. ARHL is characterized by a progressive decline in hearing sensitivity, reduced ability to understand speech in noisy environments, and impaired sound localization. Other common causes of SNHL include genetic mutations and exposure to environmental factors, such as excessive noise and ototoxic drugs. Noise exposure, in either occupational, recreational, or environmental settings, is the leading cause of preventable SNHL. It is estimated that approximately 16% of all disabling hearing loss in the adult population worldwide is attributed to occupational noise exposure, ranging from 7% to 21% across different regions (Nelson et al., 2005). Unaddressed hearing loss results in communication difficulties, which can lead to social isolation, loneliness, and depression, negatively affecting the well-being of those affected. Current interventions are limited to medical devices, such as hearing aids and cochlear implants, but these have significant limitations because the cochlea remains damaged. Recently, the antioxidant sodium thiosulfate (Pedmark) became the first U.S. Food and Drug Administration (FDA)-approved therapy to prevent hearing loss induced by cisplatin-based chemotherapy in children (Brock et al., 2018; Dhillon, 2023; FDA, September 20, 2022; Freyer et al., 2017). Unfortunately, to date, no clinically approved pharmacological treatments are available to prevent or restore other forms of hearing loss. However, a promising number of therapeutic approaches based on otoprotection, regeneration and gene correction are currently in preclinical or clinical development (see recent reviews by Schilder et al. (2019), Le Prell (2021), and Isherwood et al. (2022)).

Despite extensive research over the past several decades, the precise pathophysiological mechanisms underlying SNHL remain poorly understood. However, an overwhelming body of evidence suggests that abnormal mitochondrial function and oxidative stress in the cochlea play a central etiological role in the various types of SNHL, either inherited or acquired as a result of aging, noise exposure, and ototoxic drug administration (Böttger and Schacht, 2013; Fischel-Ghodsian et al., 2004; Kamogashira et al., 2015; Someya and Prolla, 2010). The association between mitochondrial abnormalities and disease has been well documented. Mitochondrial dysfunction is also implicated in the normal aging process and the pathogenesis of various chronic and degenerative diseases, such as neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, etc.), cardiovascular diseases (e.g., atherosclerosis), diabetes, and cancer (Lin and Beal, 2006; Pieczenik and Neustadt, 2007).

Mitochondria are membrane-bound cellular organelles that play critical roles in a variety of cellular processes, including energy (adenosine triphosphate, ATP) production, metabolism, calcium signaling, redox signaling, and apoptosis (programmed cell death) (Ott et al., 2007). Hence, mitochondria are key regulators of cell survival and death. Mitochondria serve as the major intracellular source of reactive oxygen species (ROS), which are derivatives of molecular oxygen produced as normal by-products of aerobic cellular respiration (oxidative phosphorylation). ROS include free radicals (molecular species with an unpaired electron), such as superoxide anion (O2•−) and hydroxyl radical (HO•), and nonradicals, such as hydrogen peroxide (H2O2) (Bayr, 2005). ROS are essential molecules that serve as cell signaling molecules (secondary messengers) that regulate a multitude of biological processes, including cell proliferation, gene expression, and survival (Finkel, 2011). Under physiological conditions, the cellular levels of ROS are strongly regulated by a variety of endogenous antioxidant enzymes, such as superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH), to maintain cellular homeostasis. An imbalance between the production of ROS and the level of antioxidant defense in the cell leads to a phenomenon known as oxidative stress. Oxidative stress causes irreversible ROS-mediated cellular damage to DNA, proteins, lipids, and other macromolecules, leading to impaired physiological function and cell death.

Tissues with high metabolic demands, such as the cochlea, are particularly vulnerable to the damaging effects of ROS-induced oxidative stress. In the cochlea, it is thought that excessive production of mitochondrial ROS causes oxidative damage to key mitochondrial components, such as mitochondrial DNA (mtDNA), mitochondrial membranes, and respiratory chain proteins, resulting in mtDNA mutations, lipid peroxidation, and protein oxidation, respectively (Böttger and Schacht, 2013; Fischel-Ghodsian et al., 2004; Kamogashira et al., 2015; Someya and Prolla, 2010). This leads to mitochondrial dysfunction whereby mitochondria can no longer meet the high energetic demands of the cochlear cells, causing the cells to become bioenergetically deficient. Compared to nuclear DNA (nDNA), mtDNA is more susceptible to oxidative damage due to its close proximity to the ROS-generating electron transport chain, its lack of protection from histones and other DNA-associated proteins, and its less efficient DNA repair activity against oxidative damage (Beckman and Ames, 1999; Yakes and Van Houten, 1997). Mitochondrial dysfunction facilitates further mitochondrial ROS production in a positive feedback loop, ultimately leading to the activation of apoptotic pathways in cochlear cells and subsequent hearing loss.

The outer hair cells (OHCs), one of two distinct types of sensory receptor cells located within the cochlea, are the most prominent pathological target in SNHL. OHCs play a critical role in cochlear amplification, a mechanism responsible for the exquisite sensitivity and frequency selectivity of hearing in mammals. This active mechanical amplification process is driven by a unique motor protein expressed in the OHC lateral membrane called prestin (SLC26a5) (Bavi et al., 2021; Butan et al., 2022; Futamata et al., 2022; Ge et al., 2021; Liberman et al., 2002; Zheng et al., 2000). Prestin undergoes voltage-induced molecular conformational changes that couple into robust cell length changes termed electromotility (eM) (Ashmore, 1987; Brownell et al., 1985; Kachar et al., 1986; Santos-Sacchi and Dilger, 1988; Santos-Sacchi et al., 2019; Santos-Sacchi and Tan, 2018). OHCs thus withstand constant high-energy demands and mechanical stimulations, and since their energy metabolism is primarily aerobic (Puschner and Schacht, 1997), their fate depends on mitochondrial function. A distinct population of mitochondria is physically associated with the innermost surface of the OHC lateral wall, a unique trilaminate structure in the subplasmalemmal compartment, and these are thought to be important for fueling eM (Perkins et al., 2020). Due to their lower content of antioxidants, OHCs are intrinsically more susceptible to oxidative damage, with basal OHCs more vulnerable than apical OHCs (Sha et al., 2001). In addition to OHCs, the inner hair cells (IHCs), stria vascularis, and SGNs, which are also highly metabolically active, are susceptible to mitochondrial dysfunction (McKay et al., 2015; Raimundo et al., 2012; Tan et al., 2017). In IHCs, the ribbon synapses and CaV1.3 voltage-gated calcium channels are potentially regulated by mitochondria (Zenisek and Matthews, 2000). Mitochondrial calcium stores may also play a role in the regulation of local calcium levels, which may impact the release of neurotransmitters at the IHC synapse (Castellano-Muñoz and Ricci, 2014; Lioudyno et al., 2004).

This review focuses on our current understanding of the role of mitochondrial dysfunction and oxidative stress in the development of hereditary hearing loss and various forms of acquired SNHL, including age-related, noise-induced, and ototoxic drug-induced hearing loss. Additionally, we discuss novel antioxidant therapies that have been evaluated in preclinical and clinical studies for the different forms of acquired SNHL.