Characterizing Mitochondrial Dysfunction Across Time in a Porcine model of Spinal Cord Injury

Spinal cord injury (SCI) can result in temporary or permanent alterations in sensory, motor, and autonomic functions as a result of primary mechanical damage to the spinal cord. Functional recovery is often limited due to persistent secondary injury mechanisms like inflammation, vascular breakdown, and cellular damage. Mitochondrial dysfunction is a key driver of secondary injury pathology, and while mitochondrial-targeted therapies have shown promise in rodent models of injury, functional improvements fail to translate to humans. Pigs are excellent models for understanding both the behavioral and molecular consequences of SCI because of their physiological similarity to humans, which could bridge the translational gap between rodent research and clinical implementation. To develop effective, mechanistic-based therapies, we must understand the molecular underpinnings of SCI using both male and female animal models with high translational fidelity at multiple time points after injury. To date, research on mitochondrial dysfunction following SCI has been limited to female rodent models measured acutely (6h-7d) after injury. Here, we studied mitochondrial dysfunction at three different time points in male pigs to establish a relative time course of mitochondrial impairment following SCI that may be therapeutically targeted to treat secondary complications of injury. We measured mitochondrial bioenergetic function and electron transport chain (ETC) complex activities, as well as qualified mitochondrial dynamics and oxidative damage acutely (2h), sub-acutely (24h), and chronically (9wk) after SCI in adult male pigs. The results show distinct patterns of mitochondrial dysfunction between time points with functional deficits occurring 2h post-SCI, increased mitochondrial fragmentation at 24h post-SCI, and mitochondrial recovery by 9wks post-SCI. These studies offer insight into mitochondrial changes across time in a clinically relevant animal model of SCI in hopes of bridging the translational research gap.