Mitochondria‐associated endoplasmic reticulum membranes dysfunction contributes to PARP‐1‐dependent cell death under oxidative stress in retinal precursor cells.

Autor: Yang, Yuting, Wu, Jihong, Lu, Wei, Dai, Yiqin, Zhang, Youjia, Sun, Xinghuai
Předmět:
Zdroj: Journal of Biochemical & Molecular Toxicology; Apr2023, Vol. 37 Issue 4, p1-10, 10p
Abstrakt: Persistent poly (ADP‐ribose) polymerase 1 (PARP‐1) activation has proven detrimental and can lead to PARP‐1‐dependent cell death. Mitochondria‐associated endoplasmic reticulum (ER) membranes (MAMs) serve as essential hubs for many biological pathways, such as autophagy and mitochondria fission and fusion. This study aimed to alleviate the effects of hydrogen peroxide (H2O2)‐induced persistent PARP‐1 activation and MAM dysregulation by the usage of a PARP‐1 inhibitor. Results showed that receptor‐interacting protein kinase (RIPK) 1 inhibitor (necrostatin‐1) and PARP‐1 inhibitor (olaparib) protected retinal precursor cells from H2O2‐induced death, while a pan‐caspase inhibitor (Z‐VAD‐FMK) failed to protect R28 cells. Olaparib also alleviated H2O2‐induced MAM dysregulation, as evidenced by decreased VDAC1/ITPR3 interactions and reduced mitochondrial membrane potential collapse. Additionally, olaparib also inhibited H2O2‐induced autophagy. Inhibiting autophagic flux increased MAM signaling under both normal and oxidative conditions. Furthermore, H2O2 treatment caused a reduction in the protein level of mitofusin‐2 (MFN2) in a dose‐ and time‐dependent manner. Mfn2 knockdown was found to further magnify MAM dysregulation and mitochondrial dysfunction under normal and oxidative conditions. Mfn2 overexpression surprisingly enhanced H2O2‐induced MAM signaling and failed to rescue H2O2‐induced mitochondrial dysfunction. These results indicate that MAMs probably serve as a membrane source for oxidative stress‐associated autophagy. MAM dysregulation also contributed to H2O2‐induced PARP‐1‐dependent cell death. However, more studies are required to decipher the link between the modulation of Mfn2 expression, changes in MAM integrity, and alterations in mitochondrial performances. [ABSTRACT FROM AUTHOR]
Databáze: Complementary Index
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