Programmed cell death pathways in hearing loss: A review of apoptosis, autophagy and programmed necrosis

Abstract

Programmed cell death (PCD)—apoptosis, autophagy and programmed necrosis—is any pathological form of cell death mediated by intracellular processes. Ototoxic drugs, ageing and noise exposure are some common pathogenic factors of sensorineural hearing loss (SNHL) that can induce the programmed death of auditory hair cells through different pathways, and eventually lead to the loss of hair cells. Furthermore, several mutations in apoptotic genes including DFNA5, DFNA51 and DFNB74 have been suggested to be responsible for the new functional classes of monogenic hearing loss (HL). Therefore, in this review, we elucidate the role of these three forms of PCD in different types of HL and discuss their guiding significance for HL treatment. We believe that further studies of PCD pathways are necessary to understand the pathogenesis of HL and guide scientists and clinicians to identify new drug targets for HL treatment.

Molecular Behavior of HMGB1 in the Cochlea Following Noise Exposure and in vitro

“…Specifically, as a marker of cellular damage, the increasing HMGB1 level or the release of HMGB1 in the spiral ligament indicated the activation of cell death pathways. In previous studies, noise-induced apoptosis and necroptosis in the spiral ligament cells have been elucidated, but the pyroptosis and ferroptosis have not been verified and might cause the HMGB1 release here (Wang et al, 2019;Wu et al, 2020). Therefore, our future work will focus on defining HMGB1 sources and secretion pathways in this region during noise-induced inflammation.…”

Treatment With Calcineurin Inhibitor FK506 Attenuates Noise-Induced Hearing Loss

“…The current results support our previous conclusion that low levels of oxidative stress caused by exposure to TTS-noise activate autophagy, which inhibits cell apoptosis and prevents hair cell loss by inhibiting the accumulation of ROS. On the other hand, moderate PTS noise and sPTS noise induce excessive oxidative stress, which may trigger cell death pathways, leading to sensory hair cell death (He et al, 2017;Wu et al, 2020b). Furthermore, this notion is supported by the fact that inhibition of autophagy by siLC3B pre-treatment reduces the protective effect of FK506 against noise-induced loss of OHCs and hearing function.…”

“…In the inner ear, the lower levels of oxidative stress induced by temporary threshold shift (TTS) noise exposure or lower doses of aminoglycoside treatment inhibit apoptosis and promote hair cell survival via autophagy (Yuan et al, 2015;He et al, 2017). On the other hand, excessive activation of autophagy may induce cell death (Kroemer and Levine, 2008;Bandyopadhyay et al, 2014;Wu et al, 2020b).…”

A Review on Recent Advancement on Age-Related Hearing Loss: The Applications of Nanotechnology, Drug Pharmacology, and Biotechnology

“…The executioner phase in these pathways involves the activation of caspase 3, 6 and 7, which function to destroy nuclear proteins, induce DNA and chromatin degradation, alter cytoskeleton arrangement, and disrupt cell division and communication. Ultimately, fragments of the cell are recognised and phagocytosed by epithelial cells and macrophages [ 52 , 53 ]. Both rat and mice models have been established for AHRL via d -galactose injection inducing H 2 O 2 -related oxidative stress-associated damage predominantly through mtDNA deletion and repeats, NOX overexpression, and uncoupling protein-2 (UCP2) promotion [ 54 , 55 , 56 ].…”

“…In addition to this, chronic UPR activation and ER stress eventually inhibits autophagy, increasing the degree of misfolded and damaged proteins. Finally, chronic ER stress may trigger ROS production itself via NF-κB activation [ 53 , 64 ].…”