REDOX Imbalance and Oxidative Stress in the Intervertebral Disc: The Effect of Mechanical Stress and Cigarette Smoking on ER Stress and Mitochondrial Dysfunction
Hui Li, Joshua B. Kelley, Yiqing Ye, Zhiwei Ye, Danyelle M. Townsend, Jie Zhang, Yongren Wu
Abstract
Low back pain is a widespread condition that significantly impacts quality of life, with intervertebral disc degeneration (IDD) being a major contributing factor. However, the underlying mechanisms of IDD remain poorly understood, necessitating further investigation. Environmental risk factors, such as mechanical stress and cigarette smoke, elevate reactive oxygen species levels from both endogenous and exogenous sources, leading to redox imbalance and oxidative stress. The endoplasmic reticulum (ER) and mitochondria, two key organelles responsible for protein folding and energy production, respectively, are particularly vulnerable to oxidative stress. Under oxidative stress conditions, ER stress and mitochondrial dysfunction occur, resulting in unfolded protein response activation, impaired biosynthetic processes, and disruptions in the tricarboxylic acid cycle and electron transport chain, ultimately compromising energy metabolism. Prolonged and excessive ER stress can further trigger apoptosis through ER-mitochondrial crosstalk. Given the unique microenvironment of the intervertebral disc (IVD)-characterized by hypoxia, glucose starvation, and region-specific cellular heterogeneity-the differential effects of environmental stressors on distinct IVD cell populations require further investigation. This review explores the potential mechanisms through which environmental risk factors alter IVD cell activities, contributing to IDD progression, and discusses future therapeutic strategies aimed at mitigating disc degeneration.