A Molecular Chemical Perspective: Mitochondrial Dynamics Is Not a Bystander of Cartilage Diseases.

Cartilage-related osteoarthritis (OA) and intervertebral disc degeneration (IVDD) are typical degenerative diseases that cause a heavy socioeconomic burden for lack of disease-modifying treatments. Due to the avascular and hypoxic microenvironment of cartilage, chondrocytes primarily achieve energy supply through cytoplasmic anaerobic glycolysis; thus, mitochondria, energy producers through aerobic phosphorylation, have received little attention until recently. Mitochondria carry out a crucial role in the regulation of cellular bioenergetics, metabolism, and signaling while also serving as a central platform where diverse biological processes converge, thereby contributing significantly to cellular homeostasis and cartilage physiology. Mitochondrial functionality is intertwined with mitochondrial morphology, which is determined by a dynamic balance between mitochondrial fusion and fission. Disruption of the equilibrium leads to mitochondrial dysfunction and the onset of diseases. Although the potential role of mitochondria in the pathogenesis of cartilage-related diseases has been proposed and sporadic studies have begun to focus on the underlying molecular mechanisms of mitochondrial fusion/fission, the importance of the physiological and pathological functions of mitochondrial fusion-fission dynamics in cartilage biological processes is little discussed. This review aims to bridge the gap by characterizing its interplay with mitochondrial quality control, energy metabolism, redox homeostasis regulation, cellular senescence, and apoptosis, which are all closely associated with cartilage physiology and pathology. Moreover, its role in cartilage-related diseases, especially OA and IVDD, is further discussed. This review emphasizes the emerging field of mitochondrial fusion-fission dynamics in skeletal systems and possibly provides new cues for disease control and clinical intervention.