Project Details

Description

Mitochondria perform central roles in neuronal energy production, metabolism, calcium balance and ROS signaling. The maintenance of mitochondrial health and function is indisputably critical--mitochondrial dysfunction contributes to age-associated cognitive decline and multiple neurodegenerative disorders. As such, understanding mechanisms by which neurons accomplish mitochondrial quality control is a critical goal for human health. Old or damaged mitochondria are eliminated from neurons by a process called mitophagy, which recognizes and degrades them within the neuron. We have discovered a new, and previously unknown feature of young adult C. elegans neurons--neurons can selectively throw out packets of cellular contents that can include aggregated human neurodegenerative disease proteins and/or oxidized mitochondria. Remarkably, a similar phenomenon has recently been reported in mouse brain for remote degradation of mitochondria, suggesting mito-extrusion may be a conserved component of mitochondrial quality control. We have observed that genetic impairment of mitochondrial function can increase the number of extrusion events, suggesting that dysfunctional mitochondrial might be specifically thrown out. We propose that the neuronal extrusion phenomenon constitutes a significant but currently unknown pathway by which healthy neurons maintain their functions by ridding themselves of dysfunctional mitochondria--throwing out trash, rather than degrading it onsite. We will use the powerful C. elegans model in which we can readily manipulate genes and use fluorescent reporters to track mitochondria in vivo in individual neurons to address two key initial questions about mitochondrial extrusion: 1) what types of mitochondrial dysfunction are associated with increased extrusion (ROS, fission/fusion, mitophagy impairment)?, and 2) do neurons that extrude mitochondria exhibit features of healthier aging than those that do not? ! We speculate that the neuronal trash extrusion mechanism is conserved and the dysfunction of this pathway may contribute to neuronal decline in disease and aging. Mechanistic dissection of the basic biology in a facile experimental model will provide considerable insight into a process relevant to human brain aging and neurodegenerative disease, possibly inspiring new therapies. !Description
StatusActive
Effective start/end date9/15/178/31/20

Funding

  • National Institutes of Health: $193,750.00
  • National Institutes of Health: $232,500.00

ASJC

  • Medicine(all)
  • Neuroscience(all)

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