Mitochondrial Behavior in Axon Degeneration and Regeneration

Abstract

Mitochondria are organelles responsible for bioenergetic metabolism, calcium homeostasis, and signal transmission essential for neurons due to their high energy consumption. Accumulating evidence has demonstrated that mitochondria play a key role in axon degeneration and regeneration under physiological and pathological conditions. Mitochondrial dysfunction occurs at an early stage of axon degeneration and involves oxidative stress, energy deficiency, imbalance of mitochondrial dynamics, defects in mitochondrial transport, and mitophagy dysregulation. The restoration of these defective mitochondria by enhancing mitochondrial transport, clearance of reactive oxidative species (ROS), and improving bioenergetic can greatly contribute to axon regeneration. In this paper, we focus on the biological behavior of axonal mitochondria in aging, injury (e.g., traumatic brain and spinal cord injury), and neurodegenerative diseases (Alzheimer's disease, AD; Parkinson's disease, PD; Amyotrophic lateral sclerosis, ALS) and consider the role of mitochondria in axon regeneration. We also compare the behavior of mitochondria in different diseases and outline novel therapeutic strategies for addressing abnormal mitochondrial biological behavior to promote axonal regeneration in neurological diseases and injuries.

Keywords: Alzheimer's disease; Amyotrophic lateral sclerosis; Parkinson's disease; aging; axon regeneration; mitochondria; spinal cord injury; traumatic brain injury.

Figure 1

Mitochondrial behavior in axon degeneration and regeneration. (A) Axon regeneration: Since this process requires considerable energy, mitochondrial density at distal axons is elevated to provide sufficient ATP. Not only is anterograde transport of healthy mitochondria promoted, but so too is retrograde transport of damaged mitochondria, to increase mitochondrial density at regenerative zones. SNPH knockout in TBI models, or the bulk release of SNPH cargo vesicles at AD and fALS early stages, both enhance axonal mitochondrial transport. (B) Axon degeneration: Mitochondrial dysfunction and oxidative stress occur in injured axons. When axonal mitochondrial transport is seriously impaired, damaged mitochondria aggregate at distal zones and the healthy ones fail to transport from the proximal zones to replenish ATP insufficiency. A decrease in SNPH cargo vesicle release at later stages of AD and fALS, as well as increased SNPH expression in SCI models inhibit mitochondrial transport. Moreover, axonal microtubule loss contributes to impaired axonal transport in TBI. Mitochondrial dynamics are also defective during axon degeneration. Due to increased Drp1-mediated fission in SCI, mitochondrial fragmentation is aggravated, causing mitochondrial damage. These organelle fuse with healthy mitochondria, however, most undergo mitophagy. In PD, Pink1-Parkin dependent mitophagy is defective, facilitating damaged mitochondrial accumulation and apoptotic cascades. These processes are interconnected in response to stress, and collectively lead to axon degeneration. SNPH, syntaphilin; TBI, traumatic brain injury; AD, Alzheimer's disease; fALS, familial amyotrophic lateral sclerosis; SCI, spinal cord injury; PD, Parkinson's disease.