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Mitochondrial trafficking in healthy and injured neurons

Chang, Diane T. W. (2005) Mitochondrial trafficking in healthy and injured neurons. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Mitochondria are the primary generators of ATP and are important regulators of intracellular calcium homeostasis. These organelles are dynamically transported along lengthy neuronal processes, presumably for appropriate distribution to cellular regions of increased need such as synapses. The removal of damaged mitochondria that produce harmful reactive oxygen species and promote apoptosis is also thought to be mediated by mitochondrial transport to autophagosomes. Mitochondrial trafficking is therefore important for maintaining neuronal and mitochondrial health while cessation of movement may lead to neuronal and mitochondrial dysfunctions.The demands for mitochondria differ between developing and mature neurons, and separate mitochondrial recruitment signals have been identified in each case. In the first aim, we examined how mitochondrial dynamics are affected by the development of synaptic connections in cortical neurons. We revealed reduced mitochondrial movement and elongated morphology in mature neurons which probably serve to optimize mitochondrial contact with synaptic sites.Synapses require mitochondria to supply ATP and regulate local [Ca2+]i for neurotransmission. The second aim investigated mitochondrial trafficking patterns relative to synaptic sites on axons and dendrites. We demonstrated that synapses are targets for long-term mitochondrial localization and dynamic recruitment of moving mitochondria, and that trafficking patterns are influenced by changes in synaptic activity. We also found that mitochondrial movement in dendrites is more severely impaired by neurotoxic glutamate and zinc exposures than in axons. These findings suggest a mechanism for postsynaptic dysfunction and dendritic degeneration in excitotoxicity.The third aim examined impaired mitochondrial transport as an early pathogenic mechanism in Huntington's disease. Recent studies indicate that aggregates composed of mutant huntingtin fragments hinder axonal transport by sequestering wildtype huntingtin, cytoskeletal components and molecular motors. Our studies in cortical neurons demonstrated reduced mitochondrial trafficking specifically to sites of aggregates and impeded passage of moving mitochondria by aggregates resulting in discrete regions of mitochondrial accumulation and immobilization.In summary, this dissertation provides new insight into our understanding of mitochondrial trafficking, morphology and distribution in cortical neurons that are developing, synaptically mature, acutely injured, and diseased. We conclude that mitochondrial movement is dynamic in healthy neurons and that injured neurons exhibit different manifestations of impaired movement.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Chang, Diane T. W.dtc1@pitt.eduDTC1
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairDeFranco, Donald Bdod1@pitt.eduDOD1
Committee CoChairReynolds, Ian
Committee MemberAhearn, Joseph Mjoa8@pitt.eduJOA8
Committee MemberKlein-Seetharaman,
Committee MemberZigmond, Michael Jzigmondm@upmc.eduZIGMOND
Date: 14 December 2005
Date Type: Completion
Defense Date: 9 December 2005
Approval Date: 14 December 2005
Submission Date: 13 December 2005
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Molecular Pharmacology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: cytoskeleton; fluorescence; neurodegeneration; neuronal injury; organelle transport; PSD-95
Other ID:, etd-12132005-112751
Date Deposited: 10 Nov 2011 20:10
Last Modified: 19 Dec 2016 14:38


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