PARP1 inhibition prevents oxidative stress in age-related hearing loss via PAR-Ca2+-AIF axis in cochlear strial marginal cells.

Studies have highlighted oxidative damage in the inner ear as a critical pathological basis for sensorineural hearing loss, especially the presbycusis. Poly(ADP-ribose) polymerase-1 (PARP1) activation responds to oxidative stress-induced DNA damage with pro-repair and pro-death effects resembling two sides of the same coin. PARP1-related cell death, known as parthanatos, whose underlying mechanisms are attractive research hotspots but remain to be clarified. In this study, we observed that aged rats showed stria vascularis degeneration and oxidative damage, and PARP1-dependent cell death was prominent in age-related cochlear disorganization and dysfunction. Based on oxidative stress model of primary cultured stria marginal cells (MCs), we revealed that upregulated PARP1 and PAR (Poly(ADP-ribose)) polymers are responsible for MCs oxidative death with high mitochondrial permeability transition pore (mPTP) opening and mitochondrial membrane potential (MMP) collapse, while inhibition of PARP1 ameliorated the adverse outcomes. Importantly, the PARylation of apoptosis-inducing factor (AIF) is essential for its conformational change and translocation, which subsequently causes DNA break and cell death. Concretely, the interaction of PAR and truncated AIF (tAIF) is the mainstream in the parthanatos pathway. We also found that the effects of AIF cleavage and release were achieved through calpain activity and mPTP opening, both of which could be regulated by PARP1 via mediation of mitochondria Ca2+ concentration. In conclusion, the PAR-Ca2+-tAIF signaling pathway in parthanatos contributes to the oxidative stress damage observed in MCs. Targeting PAR-Ca2+-tAIF might be a potential therapeutic strategy for the early intervention of presbycusis and other oxidative stress-associated sensorineural deafness.

Advances in Understanding the Notch Signaling Pathway in the Cochlea.

The cochlear structure is highly complex and specific, and its development is regulated by multiple signaling pathways. Abnormalities in cochlear development can lead to different degrees of loss of function. Hair cells (HCs), which are difficult to regenerate in the mature mammalian cochlea, are susceptible to damage from noise and ototoxic drugs, and damage to HCs can cause hearing loss to varying degrees. Notch, a classical developmental signaling molecule, has been shown to be closely associated with embryonic cochlear development and plays an important role in HC regeneration in mammals, suggesting that the Notch signaling pathway may be a potential therapeutic target for cochlear development and hearing impairment due to HC damage. In recent years, the important role of the Notch signaling pathway in the cochlea has received increasing attention. In this paper, we review the role of Notch signaling in cochlear development and HC regeneration, with the aim of providing new research ideas for the prevention and treatment of related diseases.

Cochlear metabolomics, highlighting novel insights of purine metabolic alterations in age-related hearing loss.

Aging is an inevitable phase in mammals that leads to health impairments, including hearing loss. Age-related hearing loss (AHL) leads to psychosocial problems and cognitive decline in the elderly. In this study, mean thresholds of auditory brainstem responses (ABR) and distortion-product otoacoustic emissions (DPOAE) increased at multiple frequencies in aged rats (14 months old) compared to young rats (2 months old). Using untargeted ultra-high performance liquid chromatography-mass spectroscopy (LC-MS), we quantified molecular metabolic markers in the cochlea of aged rats with hearing loss. A total of 137 different metabolites were identified in two groups, highlighting several prominent metabolic pathways related to purine metabolism; glycine, serine, and threonine metabolism; arginine and proline metabolism; and pyrimidine metabolism. In addition, the beneficial effects of purine supplementation were demonstrated in a mimetic model of senescent marginal cells (MCs). Overall, altered metabolic profiling is both the cause and manifestation of pathology, and our results suggest that cellular senescence and dysfunctional cochlear metabolism may contribute to the progression of AHL. These findings are seminal in elucidating the pathophysiological mechanisms underlying AHL and serve as a basis for future clinical predictions and interventions in AHL.

USP14 Positively Modulates Head and Neck Squamous Carcinoma Tumorigenesis and Potentiates Heat Shock Pathway through HSF1 Stabilization.

The ubiquitin-proteasome system is a pivotal intracellular proteolysis process in posttranslational modification. It regulates multiple cellular processes. Deubiquitinating enzymes (DUBs) are a stabilizer in proteins associated with tumor growth and metastasis. However, the link between DUBs and HNSCC remains incompletely understood. In this study, therefore, we identified USP14 as a tumor proliferation enhancer and a substantially hyperactive deubiquitinase in HNSCC samples, implying a poor prognosis prediction. Silencing USP14 in vitro conspicuously inhibited HNSCC cell proliferation and migration. Consistently, defective USP14 in vivo significantly diminished HNSCC tumor growth and lung metastasis compared to the control group. Luciferase assays indicated that HSF1 was downstream from USP14, and an evaluation of the cellular effects of HSF1 overexpression in USP14-dificient mice tumors showed that elevated HSF1 reversed HNSCC growth and metastasis predominantly through the HSF1-HSP pathway. Mechanistically, USP14 encouraged HSF1 expression by deubiquitinating and stabilizing HSF1, which subsequently orchestrated transcriptional activation in HSP60, HSP70, and HSP90, ultimately leading to HNSCC progression and metastasis. Collectively, we uncovered that hyperactive USP14 contributed to HNSCC tumor growth and lung metastasis by reinforcing HSF1-depedent HSP activation, and our findings provided the insight that targeting USP14 could be a promising prognostic and therapeutic strategy for HSNCC.

Cellular autophagy, the compelling roles in hearing function and dysfunction.

Sensorineural hearing loss (SNHL) is currently a major health issue. As one of the most common neurodegenerative diseases, SNHL is associated with the degradation of hair cells (HCs), spiral ganglion neurons (SGNs), the stria vascularis, supporting cells and central auditory system cells. Autophagy is a highly integrated cellular system that eliminates impaired components and replenishes energy to benefit cellular homeostasis. Etiological links between autophagy alterations and neurodegenerative diseases, such as SNHL, have been established. The hearing pathway is complex and depends on the comprehensive functions of many types of tissues and cells in auditory system. In this review, we discuss the roles of autophagy in promoting and inhibiting hearing, paying particular attention to specific cells in the auditory system, as discerned through research. Hence, our review provides enlightening ideas for the role of autophagy in hearing development and impairment.