Axon Regeneration and Neuronal Aging

Neurons extend axons and form synapses to communicate with distant cells. These structures make neurons face unique challenges, including supplying adequate materials to the sub-cellular area away from the cell body and maintaining structure against damage. Neurons also face particular challenges during aging because the aging condition can increase the risk of neuronal damage that can be caused by traumatic injury, stroke, and some age-associated neurodegenerative disorders. Axon regeneration is one of the essential steps in restoring the function of the damaged neurons.

Our long-term research goal is to understand how the nervous system maintains its function and integrity in response to aging and injury.

1) Systemic regulation of mitochondrial stress

Mitochondria play critical roles in aging and healthspan. In C. elegans, mitochondrial dysfunction in one organ has been linked with alterations in other remote tissues' mitochondrial stress response pathway called unfolded protein response (mitoUPR). On this basis, we investigate how mitochondria dysfunction in a subset of neurons can affect organismal aging and healthspan.

2) Mitochondria and Aging

Mitochondria positioning and function in neurons are likely to be regulated by complex interactions governing the balance of mitochondria fission/fusion, trafficking, targeting, anchoring, and quality. Many efforts have been made to identify core factors functioning in each of those processes. However, there are gaps in our knowledge of how these complex mitochondria changes are coordinated to maintain mitochondrial localization and function at specific areas of neurons, such as synapses and axons in the basal condition, and how aging and age-related disease affect it.

3) Mitochondrial function during axon regeneration and aging

Mitochondria undergo dynamic changes in their morphology, motility, number, and activity to match local energy demand and maintain cellular homeostasis. Our and others' recent studies using young model animals have demonstrated that the changes in mitochondrial dynamics and activity after axonal injury are critical determinants of axon-regeneration capacity. Growing evidence indicates that aging is a significant risk factor causing mitochondrial abnormalities in the nervous system.

We investigate 1) how aging affects mitochondrial dynamics and activity after axonal injury; 2) what the role of mitochondria in the age-related declines in axon regeneration is; 3) What molecular mechanisms control the dynamics and functions of mitochondria in response to axonal damage and aging.

GABA motor neuron 24 after axotomy. Axon injury increases mitochondrial density

Arrowheads indicate mito::mCherry. Aritesks indicate the proximal tip of injured axon.

4) Gene expression during axon regeneration and aging

The neuronal regulation of axon regeneration likely relies extensively on gene-expression changes in damaged neurons. Although several axon-injury signals regulating the transcription of injured neurons have been identified, far less is understood about how injured neurons regulate gene expression at the post-transcriptional level to affect axon regeneration.

5) Mitochondrial response to environmental toxicants

Mitochondria are important intracellular targets for environmental toxicants. Short- and long-term exposure to environmental toxins induces extensive changes in mitochondrial morphology, dynamics, physiological properties, activity, homeostasis, and interactions with other intracellular organelles. Environmental toxicity-induced mitochondrial dysfunction can interfere with an organism's health and survival. We use C. elegans as an in vivo model to investigate how mitochondria are affected by environmental contaminants and their effects on the health and longevity of the organism.