Melatonin attenuates intervertebral disc degeneration by restoring mitochondrial homeostasis through PGC-1α signaling pathway.

Abstract

Intervertebral disc degeneration (IVDD) is a major cause of low back pain (LBP) and poses a substantial economic burden worldwide. Mitochondrial dysfunction, associated with oxidative stress and apoptosis, is linked to various degenerative diseases. Melatonin has emerged as a potential therapeutic agent for preventing IVDD because of its capacity to regulate cellular rhythms. The impact of melatonin on mitochondrial dysfunction and its underlying mechanisms is not yet fully understood. Firstly, Cell Counting Kit-8 (CCK-8) assay was used to evaluate nucleus pulposus (NP) cell viability treated with melatonin and advanced oxidation protein products (AOPP). Then, Western blotting, immunofluorescence and tunnel staining were employed to explore the underlying mechanisms in vitro. Next, a needle-punctured rat model followed by radiographic analysis and immunohistochemical staining was used to evaluate the potential effect of melatonin in vivo. This study demonstrated that AOPP triggered oxidative stress, exacerbated mitochondrial injury, and increased NP cell apoptosis. Additionally, melatonin enhanced mitochondrial function and protected NP cells from oxidative injury. Further studies demonstrated that melatonin enhanced mitochondrial biogenesis and modulated mitochondrial dynamics and mitophagy via the Peroxisome proliferator-activated receptorγcoactivator 1α (PGC-1α) signaling pathway, maintaining mitochondrial homeostasis and thereby decreasing excessive apoptosis and extracellular matrix (ECM) degradation. A PGC-1α inhibitor lessened melatonin's effect on the mitochondrial quality system, weakening its protective function in NP cells against oxidative stress. Furthermore, in vivo experiments confirmed that melatonin slowed the progression of IVDD. These findings provide a theoretical basis for treating IVDD by targeting mitochondrial dysfunction and modulating the mitochondrial quality control system. Melatonin could be an effective treatment for IVDD.