PARP1 inhibition prevents oxidative stress in age-related hearing loss via PAR-Ca 2+ -AIF axis in cochlear strial marginal cells.

Autor: Wan H; Department of Otolaryngology-Head and Neck Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei Province, China; Research Institute of Otolaryngology-Head and Neck Surgery, Wuhan University, Wuhan, 430060, Hubei Province, China; The First Clinical School of Wuhan University, Wuhan, 430060, Hubei Province, China., Chen H; Department of Otolaryngology-Head and Neck Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei Province, China; Research Institute of Otolaryngology-Head and Neck Surgery, Wuhan University, Wuhan, 430060, Hubei Province, China; The First Clinical School of Wuhan University, Wuhan, 430060, Hubei Province, China., Liu J; The First Clinical School of Wuhan University, Wuhan, 430060, Hubei Province, China., Yang B; Department of Otolaryngology-Head and Neck Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei Province, China; Research Institute of Otolaryngology-Head and Neck Surgery, Wuhan University, Wuhan, 430060, Hubei Province, China; The First Clinical School of Wuhan University, Wuhan, 430060, Hubei Province, China., Zhang Y; Research Institute of Otolaryngology-Head and Neck Surgery, Wuhan University, Wuhan, 430060, Hubei Province, China; The First Clinical School of Wuhan University, Wuhan, 430060, Hubei Province, China., Bai Y; Department of Otolaryngology-Head and Neck Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei Province, China; Research Institute of Otolaryngology-Head and Neck Surgery, Wuhan University, Wuhan, 430060, Hubei Province, China; The First Clinical School of Wuhan University, Wuhan, 430060, Hubei Province, China., Chen X; Department of Otolaryngology-Head and Neck Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei Province, China; Research Institute of Otolaryngology-Head and Neck Surgery, Wuhan University, Wuhan, 430060, Hubei Province, China; The First Clinical School of Wuhan University, Wuhan, 430060, Hubei Province, China., Wang J; Department of Otolaryngology-Head and Neck Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei Province, China; Research Institute of Otolaryngology-Head and Neck Surgery, Wuhan University, Wuhan, 430060, Hubei Province, China; The First Clinical School of Wuhan University, Wuhan, 430060, Hubei Province, China., Liu T; Department of Otolaryngology-Head and Neck Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei Province, China; Research Institute of Otolaryngology-Head and Neck Surgery, Wuhan University, Wuhan, 430060, Hubei Province, China. Electronic address: rm003860@whu.edu.cn., Zhang Y; Department of Otolaryngology-Head and Neck Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei Province, China; Research Institute of Otolaryngology-Head and Neck Surgery, Wuhan University, Wuhan, 430060, Hubei Province, China. Electronic address: zyy-ent@whu.edu.cn., Hua Q; Department of Otolaryngology-Head and Neck Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei Province, China; Research Institute of Otolaryngology-Head and Neck Surgery, Wuhan University, Wuhan, 430060, Hubei Province, China. Electronic address: hqq1214@whu.edu.cn.
Jazyk: angličtina
Zdroj: Free radical biology & medicine [Free Radic Biol Med] 2024 Aug 01; Vol. 220, pp. 222-235. Date of Electronic Publication: 2024 May 10.
DOI: 10.1016/j.freeradbiomed.2024.05.020
Abstrakt: 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 Ca 2+ concentration. In conclusion, the PAR-Ca 2+ -tAIF signaling pathway in parthanatos contributes to the oxidative stress damage observed in MCs. Targeting PAR-Ca 2+ -tAIF might be a potential therapeutic strategy for the early intervention of presbycusis and other oxidative stress-associated sensorineural deafness.
Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships.
(Copyright © 2024 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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