Cyclic tensile loading regulates nucleus pulposus cell autophagy through mitochondrial dynamics: molecular mechanisms and implications

Chronic low back pain is predominantly driven by intervertebral disc degeneration (IVDD), a process rooted in the dysregulation of extracellular matrix (ECM) homeostasis within nucleus pulposus (NP) cells. These cells reside in a harsh microenvironment characterized by hypoxia, nutrient scarcity, and mechanical stress, making the regulatory pathways of autophagy and mitochondrial dynamics critical for their survival and function. This review synthesizes current evidence demonstrating that cyclic tensile loading (CTL) is a decisive factor directing NP cell fate through the coupling of mitochondrial fission–fusion dynamics and autophagic flux. We delineate a dual mechano-response: moderate, physiological CTL (approximately 5–10% strain, based primarily on in-vitro models) promotes cytoprotective autophagy and mitochondrial fusion via AMPK/mTOR and integrin–FAK signaling, supporting ECM synthesis. This involves activation of TFEB-driven lysosomal biogenesis and PINK1–Parkin-mediated mitophagy. Conversely, supraphysiological, pathological CTL (> 15–20% strain) triggers DRP1-dependent mitochondrial fission, activates PINK1–Parkin pathways alongside ROS/JNK signaling, and induces BNIP3-associated autophagic dysfunction. This cascade leads to inflammasome activation, cellular senescence, apoptosis, and ultimately ECM catabolism. We further dissect key molecular transducers, including Piezo1, HIF-1α/BNIP3, and the cytoskeleton, which convert mechanical stimuli into autophagic responses. The pivotal duality of autophagy—protective versus cytotoxic—is shown to hinge on the maintenance of mitochondrial dynamic equilibrium, the disruption of which accelerates IVDD. The integration of biomechanical, mitochondrial, and autophagic axes provides a novel framework for understanding IVDD pathogenesis. This synthesis identifies promising therapeutic targets, such as DRP1, mitophagy regulators, and SIRT3, which have shown potential in preclinical models to decouple pathological mechano-signaling and preserve NP cell function. The review establishes a mechanistic rationale for developing interventions aimed at halting IVDD progression by modulating the cellular response to mechanical stress.