Unraveling the Therapeutic Potential of a Small Molecule Activator of Mitochondrial Fusion and Mechanistic Role of Mitochondria in Axon Regeneration

Project: Research

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Description

Nervous system injury is the leading cause of motor dysfunction without effective treatments. Unlike the central nervous system (CNS), peripheral nerves (PN) of the peripheral nervous system (PNS) are regenerating well, albeit at a slow rate (1mm/day). In humans, corticospinal tracts (CNS) and sciatic nerves (PNS) contain long processes of axons over 1 meter long. Axon (make up the nerves) regeneration is an energy-demanding process that requires long-distance axonal transport of mitochondria from soma to regenerating axons, where local energy consumption is critical. Mitochondria are energy plants undergo frequent fusion, fission, and bi-directional axonal transport. Increasing evidence suggests that defective mitochondrial dynamics is a common pathologic mechanism across various nervous system injuries. Fusion and fission proteins mutations associated with development of neurodegenerative diseases. Mitochondria are mostly stationary in uninjured PNS axons. However, faster axonal mitochondrial transport is observed only in regenerating axons. Mitochondria are heavily localized into neuromuscular junction where successful muscle reinnervation is required for full motor functional recovery. In young CNS neurons, axonal mitochondria are highly mobile and move bi-directionally to meet high-energy demand of growing cells; however, this dynamics movement loss as neurons matured. These studies form the basis of our hypothesis that lack of mitochondrial mobility corresponds directly with a decline in regenerative capacity that can be targeted to facilitate axon regeneration. To test this hypothesis, we first demonstrated that a known regeneration-associated geneHsp27not only accelerated axon regeneration, but also increased mitochondrial axonal transport and size as well as increased localization of fusion proteins into regenerating axons. We then showed that a commercial mitochondrial fusion activator M1 small molecule induced clustering of larger mitochondria and fusion proteins, and accelerating axonal mitochondrial transport at the growing tip of regenerating axons. More importantly, M1 substantially increased axon regeneration in injured PNS neurons in cultures andin vivo. Current proposal aims to test therapeutic potential of M1 in treating severe PNS and CNS injuries. We will first optimize treatment paradigm of M1 after PN injury, and examine functional recovery after repeated PN crushes (severe injury). We will study axon regeneration in CNS neurons using retinal ganglion cells and animal model of optic nerve injury. Finally, we will elucidate underling mechanisms of M1 in preserving mitochondrial membrane potential of PNS and CNS neurons by live-cell imaging. Current study provides insight into the development of mitochondria-based therapy direct at modulating mitochondrial dynamics for successful axon regeneration and functional recovery. 

Detail(s)

Project number9042787
Grant typeGRF
StatusActive
Effective start/end date1/01/20 → …