Effect of mitochondrial dysfunction on scar formation after spinal cord injury

Spinal cord injury (SCI) triggers a cascade of primary and secondary pathological events that culminate in the formation of glial and fibrotic scars, which constitute a major barrier to axonal regeneration and functional recovery. Emerging evidence highlights mitochondrial dysfunction as a central driver of this process. Mitochondria are essential for sustaining ATP production, maintaining redox balance, and regulating calcium homeostasis. Following SCI, direct mechanical disruption, oxidative stress, and calcium overload impair mitochondrial integrity, leading to energy metabolism collapse, excessive reactive oxygen species (ROS) accumulation, and disrupted mitochondrial dynamics. These alterations promote reactive gliosis, fibroblast activation, and maladaptive extracellular matrix deposition. Furthermore, defective mitophagy amplifies neuroinflammation and glial scar consolidation through the PINK1/Parkin and BNIP3/NIX pathways. Recent advances in mitochondrial-targeted therapies-including antioxidants (MitoQ, SS-31), metabolic modulators (AMPK agonists, NAD⁺ precursors), and strategies enhancing fusion or mitophagy-have demonstrated promising results in reducing scar formation and promoting neural repair. In addition, cutting-edge approaches such as mitochondrial transplantation, stem cell-derived mitochondrial transfer, and CRISPR-based mitochondrial gene editing provide new opportunities for restoring mitochondrial homeostasis. This review summarizes the multifaceted roles of mitochondrial dysfunction in SCI-induced scar formation and discusses novel therapeutic strategies targeting mitochondrial metabolism and dynamics to enhance neural regeneration.