Mitochondrial regulatory mechanisms in spinal cord injury: A narrative review

Abstract

Spinal cord injury is a severe central nervous system injury that results in the permanent loss of motor, sensory, and autonomic functions below the level of injury with limited recovery. The pathological process of spinal cord injury includes primary and secondary injuries, characterized by a progressive cascade. Secondary injury impairs the ability of the mitochondria to maintain homeostasis and leads to calcium overload, excitotoxicity, and oxidative stress, further exacerbating the injury. The defective mitochondrial function observed in these pathologies accelerates neuronal cell death and inhibits regeneration. Treatment of spinal cord injury by preserving mitochondrial biological function is a promising, although still underexplored, therapeutic strategy. This review aimed to explore mitochondrial-based therapeutic advances after spinal cord injury. Specifically, it briefly describes the characteristics of spinal cord injury. It then broadly discusses the drugs used to protect the mitochondria (e.g., cyclosporine A, acetyl-L-carnitine, and alpha-tocopherol), phenomena associated with mitochondrial damage processes (e.g., mitophagy, ferroptosis, and cuproptosis), mitochondrial transplantation for nerve cell regeneration, and innovative mitochondrial combined protection therapy.

Deciphering the neuroprotective mechanisms of RACK1 in cerebral ischemia‐reperfusion injury: Pioneering insights into mitochondrial autophagy and the PINK1/Parkin axis

“… 48 These insights align with previous research emphasizing the significant role of mitophagy in various neurological conditions, further supporting its important contribution to maintaining mitochondrial equilibrium and function, which is essential for neural injury recuperation. 49 , 50 , 51 , 52 …”

Neurotrauma—From Injury to Repair: Clinical Perspectives, Cellular Mechanisms and Promoting Regeneration of the Injured Brain and Spinal Cord

“…Rises in intracellular Ca 2+ , typically due to excitotoxicity or oxidative stress, act as an initiator of mitochondrial crises. Mitochondrial Na + /Ca 2+ exchange channel activity permits Ca 2+ entry into the mitochondria, with rising intra-mitochondrial calcium leading to opening of the mitochondrial permeability transition pore (mPTP), mitochondrial oedema and swelling, loss of mitochondrial membrane potential and severe disruption of ATP synthesis [ 99 , 100 , 101 ]. This membrane damage results in the release of mitochondrial proteins such as cytochrome c, Ca 2+ and reactive oxygen species (ROS) into the cytosol, which in turn can trigger apoptosis [ 101 ].…”

“…Dysfunctional mitochondrial activity results in the release of ROS, or free radicals. In states such as neurotrauma, where ROS and RNS production is confluent, production far outstrips any antioxidant/scavenger capacity [ 99 , 101 ]. Mitochondrial production of nitric oxide (NO) and electron leakage from the electron transport chain (ETC) to produce superoxide radicals (O −2 ) result in the formation of peroxynitrite (PN).…”

“…Mitochondrial production of nitric oxide (NO) and electron leakage from the electron transport chain (ETC) to produce superoxide radicals (O −2 ) result in the formation of peroxynitrite (PN). PN and other potent oxidising agents propagate mitochondrial damage via lipid peroxidation, leading to mitochondrial DNA damage [ 99 ]. This mediates further disruption of the mitochondrial structure, allowing the release of ROS, which results in the destruction of cellular structures, proteins and lipids, triggering apoptotic pathways, the release of pro-inflammatory mediators and perpetuating secondary injury [ 68 ].…”