Mitochondrial dysfunction as a target in spinal cord injury: Intimate correlation between pathological processes and therapeutic approaches

SCHMIDT, JULIETA; H.R QUINTÁ

NEURAL REGENERATION RESEARCH

SHENYANG EDITORIAL DEPT NEURAL REGENERATION RES

Año: 2023

1673-5374

Traumatic spinal cord injuries (SCI) interrupt the connection of allaxonal projections with their neuronal targets below and above the lesion site.This interruption results in either temporary or permanent alterations in thelocomotor, sensory, and autonomic functions. Damage inthe spinal tissue prevents the re-growth of severed axons across the lesion andtheir reconnection with neuronal targets. Therefore, the absence of spontaneousrepair leads to sustained impairment in voluntary control of movement below theinjury. For decades, axonal regeneration and reconnection have beenconsidered the opitome of SCI repair with the goal being the repair of the damagedlong motor and sensory tracts in a complex process that involves the: 1) resealinginjured axons; 2) reconstructing the cytoskeletal structure inside axons; 3)re-establishinghealthy growth cones; and 4) assembling axonal cargos. These biologicalprocesses require an efficient production of Adenosine triphosphate (ATP), whichis affected by mitochondrial dysfunction after SCI.From a pathological standpoint, during the secondary stage of SCI,mitochondrial homeostasis is disrupted, mainly in the distal segments of severedaxons. This result in a reduction of ATP levels and subsequent inactivation of ATP-dependention pumps required for regulation of ion concentrations and reuptake of neurotransmitters,such as glutamate. The consequences are calcium overload, reactive oxygen species(ROS) formation, and excitotoxicity. These events are intimately related to theactivation of necrotic and apoptotic cell death programs, and further exacerbatethe secondary stage of the injury, being a hallmark of SCI.This is why restoring mitochondrial function during the early stage ofsecondary injury could represent a potentially effective therapeuticintervention to overcome the motor and sensory failure produced by SCI.This reviewdiscusses the most recent evidence linkingmitochondrial dysfunction with axonal regeneration failure in the context of SCI.It also covers the future of mitochondria-targeted therapeutical approaches,such as antioxidant molecules, removing mitochondrial anchor proteins, andincreasing energetic metabolism through creatine treatment. These approachesare intended to enhance functional recovery by promoting axonal regeneration-reconnectionafter SCI.