The dual role of poly(ADP-ribose) polymerase-1 in modulating parthanatos and autophagy under oxidative stress in rat cochlear marginal cells of the stria vascularis

Abstract

Oxidative stress is reported to regulate several apoptotic and necrotic cell death pathways in auditory tissues. Poly(ADP-ribose) polymerase-1 (PARP-1) can be activated under oxidative stress, which is the hallmark of parthanatos. Autophagy, which serves either a pro-survival or pro-death function, can also be stimulated by oxidative stress, but the role of autophagy and its relationship with parthanatos underlying this activation in the inner ear remains unknown. In this study, we established an oxidative stress model in vitro by glucose oxidase/glucose (GO/G), which could continuously generate low concentrations of H2O2 to mimic continuous exposure to H2O2 in physiological conditions, for investigation of oxidative stress-induced cell death mechanisms and the regulatory role of PARP-1 in this process. We observed that GO/G induced stria marginal cells (MCs) death via upregulation of PARP-1 expression, accumulation of polyADP-ribose (PAR) polymers, decline of mitochondrial membrane potential (MMP) and nuclear translocation of apoptosis-inducing factor (AIF), which all are biochemical features of parthanatos. PARP-1 knockdown rescued GO/G-induced MCs death, as well as abrogated downstream molecular events of PARP-1 activation. In addition, we demonstrated that GO/G stimulated autophagy and PARP-1 knockdown suppressed GO/G-induced autophagy in MCs. Interestingly, autophagy suppression by 3-Methyladenine (3-MA) accelerated GO/G-induced parthanatos, indicating a pro-survival function of autophagy in GO/G-induced MCs death. Taken together, these data suggested that PARP-1 played dual roles by modulating parthanatos and autophagy in oxidative stress-induced MCs death, which may be considered as a promising therapeutic target for ameliorating oxidative stress-related hearing disorders.

PARP1 promote autophagy in cardiomyocytes via modulating FoxO3a transcription

“…Autophagy is closely related with cell death and apoptosis in eukaryotic organisms 31 . Although it is proved that PARP1 activation plays a curial role in oxidative stress-induced cell death 32 , the precise understanding of underlying mechanisms remains elusive. Here we report several new and important findings.…”

Metformin attenuates the D‑galactose‑induced aging process via the UPR through the AMPK/ERK1/2 signaling pathways

“…S3). The cell counting kit-8 (ccK-8) assay (dojindo Laboratories) was used to determine the cell viability and cell proliferation according to the manufacturer's instructions and as previously described (16). d-gal was used to induce senescence in the Pc12 cells, which were pre-treated with compound c (40 µmol/l), U0126 (10 µmol/l) or metformin (100 µmol/l) for 24 h for further experiments.…”

Baicalin attenuates gentamicin‐induced cochlear hair cell ototoxicity

“…It is worth noting that cleaved‐PARP‐1 can take part in various forms of cell death, e.g., necrosis, autophagy and parthanatos due to its multifaceted roles. Moreover, it has been reported that specific apoptosis inhibitors often function in a type‐ and stimulus‐specific manner (Chaudhuri & Nussenzweig, ; Jiang et al, ). Therefore, whether another form of cell death is involved in baicalin‐mediated alleviation of GM‐induced cochlear hair cell ototoxicity needs further detailed analysis.…”