The role and regulation of mitochondrial localization in mature neurons.

PROJECT SUMMARY/ABSTRACT Dynamic regulation of mitochondrial localization is vital for the various energy demands and homeostasis maintenance of subcellular regions. Key components governing mitochondrial motility, dynamics, anchoring, and quality control have been identified. However, little is known about the signaling mechanisms by which neurons coordinate mitochondrial localization in the short and long term in response to environmental and physiological stimuli. This proper regulation of mitochondrial localization is particularly important in neurons with unique and elongated structures that lead to a fundamental problem of a mismatch between the mitochondrial biosynthesis site (cell body) and the high-demanding site for mitochondrial function (axon and synapse). Growing evidence indicates that an irregular mitochondrial localization to the axon and synapse is closely associated with many neurological disorders, including Alzheimer's disease, nerve degeneration, and regeneration failure. This proposal aims to elucidate how neurons regulate mitochondrial localization in two fundamental conditions including age and injury. In addition, we propose to determine how the regulation of mitochondrial localization affects the maintenance of neuronal function against injury and aging. This proposal is built based on recent in vivo studies that adult neurons undergo progressively reduced mitochondrial movement. Our lab and others have also revealed that injured neurons acutely change mitochondrial movement and localization, determining axon regeneration ability. The underlying mechanisms by which neurons regulate mitochondrial localization in aging and injury conditions remain poorly understood. Lack of this knowledge hinders the development of therapeutic strategies for neurological diseases such as Alzheimer's disease and nerve injury that have been associated with abnormal mitochondrial localization. We combine Caenorhabditis elegans genetics, mitochondrial biology, innovative in vivo imaging, and laser axotomy to address these unmet needs. Our preliminary data suggest that the DLK-1 MAPK signaling, a conserved pathway associated with synapse development, axon regeneration, and progressive neurodegeneration in Alzheimer's disease model, could be a novel regulator of mitochondrial localization in neurons. This proposal consists of three specific aims to answer how neurons regulate mitochondrial localization in aging and injury conditions (Aim 1), what the role of mitochondria in the recovery of the adult neurons after injury (Aim 2), and how the communication between mitochondria and nucleus controls the DLK-1 signaling, thereby mitochondria function and axon regeneration (Aim 3). We expect that our proposed experiments will achieve a new understanding of the mechanisms that maintain the optimal function of the nervous system by regulating mitochondrial function in aging and injured neurons. Also, our findings will provide better insight into novel therapeutic approaches to restoring neuronal function after nerve injury.