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Mitochondrial DNA in neurons and its modulation by neurotoxins

Santos, Maria Soledad (2006) Mitochondrial DNA in neurons and its modulation by neurotoxins. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Mitochondria are essential for the function of all mammalian tissues, serving functions, such as ATP generation. Neurons are highly dependent on ATP production and consume more energy than other cells for their metabolism. Mitochondria are semi-autonomous organelles that contain their own DNA (mtDNA). Mutations and deletions in mtDNA lead to mitochondrial dysfunction that compromise neuronal viability. From the many approaches taken to investigate the role of mitochondria in neurodegeneration; however, few have focused on mtDNA dynamics.First, I investigated whether mtDNA replication impairment plays a role in neurotoxicity. For this purpose, I tested two neurotoxins, glutamate and rotenone, which induce neuronal damage by different mechanisms. Our results show that mitochondrial dysfunction induced by different neurotoxins does not correlate with effects on mtDNA replication. Glutamate, at excitotoxic concentrations, does not affect mtDNA replication while rotenone induces a time and concentration dependent decrease of mtDNA replication. Also, rotenone effect on mtDNA replication seems to be independent of its acute toxic effect.Several mechanisms have been proposed as responsible for rotenone's toxicity, such as complex I inhibition and increased ROS production. Our experiments ruled out the implication of these two mechanisms in rotenone-induced mtDNA replication decrease. Mitochondrial nucleotides are key regulators of mtDNA replication. However, our experiments show that rotenone effect on mtDNA replication does not correlate with mitochondrial nucleotide imbalances. Therefore, our results suggest that rotenone-induced mtDNA replication decrease is mediated by a yet to be described mechanism.Mitochondrial function requires the coordination of all processes that take place at this organelle. I studied if a reduction in mtDNA replication could have an effect on mitochondrial membrane potential, movement and morphology. Experiments with rotenone treatments that reduce mtDNA replication have demonstrated that mtDNA replication decrease does not correlate with overall mitochondrial dysfunction at the time points used in this study.In summary, this dissertation provides a first attempt to study the dynamics of mtDNA upon neurotoxin exposure. I conclude that rotenone decreases mtDNA replication in the absence of overt toxicity. This effect could play an important role in its long term effects as neurons could accumulate mitochondria with decreased mtDNA content.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Santos, Maria Soledadmas116@pitt.eduMAS116
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairDeFranco, Donald Bdod1@pitt.eduDOD1
Committee MemberMathews, Clayton E.cem65@pitt.eduCEM65
Committee MemberAizenman, Eliasredox@pitt.eduREDOX
Committee MemberReynolds, Ian
Committee MemberWang, Qiming J.qjw1@pitt.eduQJW1
Date: 28 June 2006
Date Type: Completion
Defense Date: 27 February 2006
Approval Date: 28 June 2006
Submission Date: 4 June 2006
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: ; real-time PCR
Other ID:, etd-06042006-190854
Date Deposited: 10 Nov 2011 19:46
Last Modified: 15 Nov 2016 13:44


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