Axon regeneration is one of the essential processes that restore the nervous system after nerve injury and neurodegeneration. Aging decreases axon-regeneration capacity while increasing the risk of axonal damages. Failure of axonal regeneration following nerve injury can lead to permanent body-movement impairment and various disabilities. Very little is known about the underlying mechanism of axon regeneration, and there is no efficient treatment to enhance the function of damage neurons. The goal of this proposal is to identify an intrinsic mechanism underlying the age-related decline of axon regeneration by investigating the responses of mitochondria to axonal damage and aging. Mitochondria dynamically change in their morphology, motility, number, and activity by communicating with the nucleus of the host cell to match local demand for energy and to maintain cellular and their own homeostasis. Our and others' recent studies have found a clear link between axon-regeneration capacity and mitochondrial behavioral changes in response to axonal damage. Our unpublished studies also suggest that axon regeneration is regulated by ATFS-1, a key factor in the retrograde signaling from mitochondria to nucleus that mediates mitochondrial unfolded protein response (mitoUPR). Adjusting mitochondrial response to axonal damage could therefore be a critical determinant of axon regeneration. We do not know, however, the underlying mechanisms of these mitochondrial responses to axonal damage and their roles in the age-related decline of axon regeneration. To delineate these unmet needs, we will combine our expertise in C. elegans genetics, mitochondrial biology, and in vivo laser axotomy at a single axon resolution. Specifically, we will use in vivo imaging approaches to monitor the axonal trafficking of mitochondria and the activity of mitoUPR after axonal damage and during aging on short-term and long-term scales. We will also use both in vivo and in vitro assays to quantitatively measure the physiological properties of mitochondria that are altered by axonal injury signals and mitoUPR (Aim 1). We will use a laser-based axotomy and genetic approaches experimentally to change the nature of mitochondria in aging animals to test the correlation with axon regeneration ability (Aim 2). Finally, we will perform visual-based genetic approaches to discover a genetic mechanism that mediates mitochondrial localization and traffic in neurons (Aim 3). We believe that these approaches will achieve a new understanding of the mechanisms that maintain optimal function of the nervous system during aging by regulating mitochondrial function in aging and injured neurons. Our findings will provide better insight into novel therapeutic approaches to restore neuronal function after nerve injury.
Failure of axonal injury can lead to irreversible loss of the nervous system function. Our research focuses on new concepts and methods to determine the role of mitochondria during regeneration of injured axons and to elucidate underlying mechanisms that link alterations in mitochondrial behavior and homeostasis and axon regeneration of aging neurons. This research will identify mitochondria as a novel therapeutic target to improve axon regeneration and potentially to treat neurodegenerative diseases that have been associated with mitochondrial abnormalities and aging.
