Reactive Oxygen Species Regulate Endoplasmic Reticulum Stress and ER-Mitochondrial Ca(2+) Crosstalk to Promote Programmed Necrosis of Rat Nucleus Pulposus Cells under Compression.
Reactive Oxygen Species Regulate Endoplasmic Reticulum Stress and ER-Mitochondrial Ca(2+) Crosstalk to Promote Programmed Necrosis of Rat Nucleus Pulposus Cells under Compression.
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DOI：
10.1155/2021/8810698
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发表时间：
2021
影响因子：
--
通讯作者：
Shao Z
中科院分区：
文献类型：
--
作者：
Lin H;Peng Y;Li J;Wang Z;Chen S;Qing X;Pu F;Lei M;Shao Z
过度压迫引起的髓核(NP)细胞程序性坏死是椎间盘退变(IVDD)发病机制中的重要因素。内质网(ER)和线粒体是细胞死亡信号通路的重要调节者，它们参与了IVDD的研究。然而，内质网应激(ERS)和内质网-线粒体相互作用在压迫诱导NP细胞程序性坏死中的具体作用尚不清楚。我们的研究表明，压缩增强了NP细胞的ERS以及内质网和线粒体之间的联系。通过抑制三磷酸肌醇受体、葡萄糖调节蛋白75、电压依赖性阴离子选择通道1复合体(IP3R-GRP75-VDAC1复合体)抑制ERS或通过抑制ER-线粒体钙离子串扰来保护NP细胞免受与聚(ADP-核糖)聚合酶(PARP)凋亡诱导因子(AIF)途径相关的程序性坏死。此外，过多的活性氧是ERS的关键激活剂，导致线粒体Ca~(2+)积聚，进而导致程序性坏死。这些数据表明，ERS和ER-线粒体钙离子串扰可能是治疗IVDD相关疾病的潜在治疗靶点。这些发现为IVDD潜在的分子机制提供了新的见解，并可能提供新的治疗靶点。
Programmed necrosis of nucleus pulposus (NP) cells caused by excessive compression is a crucial factor in the etiopathogenesis of intervertebral disc degeneration (IVDD). The endoplasmic reticulum (ER) and mitochondria are crucial regulators of the cell death signaling pathway, and their involvement in IVDD has been reported. However, the specific role of ER stress (ERS) and ER-mitochondria interaction in compression-induced programmed necrosis of NP cells remains unknown. Our studies revealed that compression enhanced ERS and the association between ER and mitochondria in NP cells. Suppression of ERS via 4-phenylbutyrate (4-PBA) or ER-mitochondrial Ca2+ crosstalk by inhibiting the inositol 1,4,5-trisphosphate receptor, glucose-regulated protein 75, voltage-dependent anion-selective channel 1 complex (IP3R–GRP75–VDAC1 complex) protected NP cells against programmed necrosis related to the poly(ADP-ribose) polymerase (PARP) apoptosis-inducing factor (AIF) pathway. Moreover, excessive reactive oxygen species are critical activators of ERS, leading to mitochondrial Ca2+ accumulation and consequent programmed necrosis. These data indicate that ERS and ER-mitochondrial Ca2+ crosstalk may be potential therapeutic targets for the treatment of IVDD-associated disorders. These findings provide new insights into the molecular mechanisms underlying IVDD and may provide novel therapeutic targets.
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