Mitochondrial Dysfunction and Endoplasmic Reticulum Stress in Chronic Pain

Abstract

Highlights What are the main findings? Defective mitochondrial function acts as a foundational trigger in the pathogenesis of chronic pain. ER stress drives the pathogenesis of chronic pain by altering neural circuit architecture and triggering the reactivity of both astrocytes and microglia. These cellular interactions underscore the critical role of ER-mediated neuroinflammation in sustaining persistent pain states. What are the implications of the main findings? Integrating mitochondrial dysfunction and ER stress into a unified pathological axis may provide a useful framework for identifying shared molecular drivers of chronic pain and developing more precise therapeutic strategies. Deciphering the ER-mitochondrial crosstalk will open a new avenue for targeted therapeutic interventions aimed at reversing organelle-level distress in chronic pain. Abstract Chronic pain is a major global health burden and often remains difficult to treat with current therapies, which frequently provide incomplete relief and may cause systemic side effects. As essential organelles in eukaryotic cells, mitochondria facilitate ATP synthesis and serve as key regulators of calcium homeostasis and apoptosis. Evidence points to mitochondrial dysfunction not merely as a result of trauma, but as a fundamental factor in why pain becomes persistent. On the other hand, the endoplasmic reticulum (ER) is more than just a structural component of the cell; it is a multi-functional organelle responsible for protein quality control, including folding and degradation, as well as lipid production and calcium signaling. ER dysfunction is a primary driver of various pathologies, such as cardiovascular disease, cancer, and neurodegenerative disorders. The organelle’s ability to execute its vital functions is strictly dependent on sufficient levels of ATP. Because mitochondrial and ER functions are closely interconnected through calcium exchange, ATP-dependent protein homeostasis, oxidative stress, and mitochondria-associated ER membranes, their dysfunction may act together to amplify nociceptive sensitization and pain chronification. In this review, we summarize current evidence linking mitochondrial dysfunction, ER stress, and ER-mitochondrial crosstalk to the pathogenesis of chronic pain and discuss their potentials as therapeutic targets.