Trafficking and Turnover in Neuronal Axons
Access StatusFull text of the requested work is not available in DASH at this time ("dark deposit"). For more information on dark deposits, see our FAQ.
MetadataShow full item record
CitationAshrafi, Ghazaleh. 2014. Trafficking and Turnover in Neuronal Axons. Doctoral dissertation, Harvard University.
AbstractNeurons are metabolically active cells that depend on mitochondria for ATP production and calcium homeostasis. Within a single neuron, the demand for mitochondrial function is highly variable both spatially and temporally. This need-based distribution is reflected in high local density of mitochondria at presynaptic endings, post-synaptic densities, nodes of Ranvier, and in growth cones, where mitochondrial function is required to sustain neuronal activity. To meet local demand, mitochondria are mobile organelles that move along microtubule cytoskeleton in axons and dendrites. Due to their role in oxidative phosphorylation, mitochondria are prone to oxidative damage that can in turn jeopardize the cell. To minimize cellular damage, an autophagic process, known as mitophagy, has evolved to clear dysfunctional mitochondria. Defects in mitochondrial clearance are implicated in neurodegenerative diseases such as Parkinson's disease (PD). In neurons, it was thought that mitochondria with reduced membrane potential are retrogradely transported to the soma where they are degraded. In this dissertation, I present a new paradigm where damaged mitochondria are arrested and undergo mitophagy locally in axons.
In chapter 2 we report that mitochondrial damage causes arrest of mitochondrial motility in neuronal axons through the action of Parkin, an E3 ubiquitin ligase implicated in PD. Parkin accumulates on the surface of depolarized mitochondria and triggers proteosomal degradation of the mitochondrial motor adaptor protein, Miro, thereby detaching mitochondria from the kinesin and dynein motor complex. This arrest of mitochondria would serve to quarantine them in preparation for their subsequent degradation.
In chapter 3, I demonstrate that damage to a small population of axonal mitochondria triggers a pathway of mitophagy that occurs locally in distal axons. Two PD-associated proteins, PINK1, a mitochondrial kinase mutated, and Parkin are both required for axonal mitophagy.
In chapter 4, I present preliminary studies examining the turnover rate of neuronal PINK1 in order to characterize its mechanism of activation in distal axons. In conclusion, I have characterized a pathway for quality control of mitochondria in neuronal axons showing that clearance of defective mitochondria oocurs locally in distal axons without a need for their retrograde transport to the soma.
Citable link to this pagehttp://nrs.harvard.edu/urn-3:HUL.InstRepos:13070049
- FAS Theses and Dissertations