Reactive Oxygen Species Regulate Endoplasmic Reticulum Stress and ER-Mitochondrial Ca2+ Crosstalk to Promote Programmed Necrosis of Rat Nucleus Pulposus Cells under Compression

Abstract

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.