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Neuronal Survival after Traumatic Brain Injury: Cardiolipin-a Critical Target

Ji, Jing (2012) Neuronal Survival after Traumatic Brain Injury: Cardiolipin-a Critical Target. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Traumatic brain injury (TBI) is a serious healthcare problem in the United States, with more than 400,000 individuals hospitalized each year and an estimated annual cost of $25 billion; thus TBI is an enormous socioeconomic burden and has significant public health relevance. TBI leads to both direct mechanical damage and functional disturbance in mitochondria, which are key mechanisms contributing to neuronal death after TBI. Therefore, prevention of mitochondrial damage and/or removal of dysfunctional mitochondria (mitophagy) are promising therapeutic strategies. Indeed, in the in vitro model of mechanical stretch injury, mitophagy was observed as early as 1 h and continued for 24 h; however, neuronal death did not occur until 6 h after the insult. The delayed emergence of neuronal death suggests a possible window of opportunity for targeted therapies. In the current research, we studied the role of cardiolipin (CL), a unique mitochondria inner membrane phospholipid, in neuronal death induced by TBI. Manipulation of neuronal CL levels by knocking down CL synthase (CLS, the rate limiting enzyme in the synthesis of CL) using siRNA technology produced 15% and 46% decrease in CL content at 72 h and at 96 h, respectively, without alteration in mitochondrial morphology or function and CL molecular speciation. CLS/CL deficiency markedly inhibited both mechanical stretch induced mitophagy and neuronal death. Using a model of direct mitochondrial injury (rotenone, complex I inhibitor), we reported that mitophagy resulted in externalization of CL to the mitochondrial outer membrane in the primary neurons and suggested redistribution of cardiolipin serves as a mitochondrial “eat-me” signal. Using global lipidomics analysis we showed that TBI induced neuronal death was accompanied by oxidative consumption of polyunsaturated CL and accumulation of more than 150 new oxygenated molecular species in CL. By applying the novel brain permeable mitochondria-targeted electron-scavenger-hemigramicidin nitroxide, we fully prevented CL oxygenation in the brain, achieved a substantial reduction in neuronal death both in vitro and in vivo, and markedly reduced behavioral deficits. Taken together, the results from doctoral work explored the role of CL after TBI that represents a novel target for neuro-drug discovery.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Ji, Jingtojijing@gmail.com
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairBayır, Hülyabayihx@ccm.upmc.edu
Committee CoChairKagan, Valerian E.kagan@pitt.eduKAGAN
Committee MemberPitt, Bruce R.brucep@pitt.eduBRUCEP
Committee MemberKochanek, Patrick M.pak6@pitt.eduPAK6
Date: 30 January 2012
Date Type: Completion
Defense Date: 5 December 2011
Approval Date: 30 January 2012
Submission Date: 28 November 2011
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Number of Pages: 136
Institution: University of Pittsburgh
Schools and Programs: Graduate School of Public Health > Environmental and Occupational Health
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: cardiolipin; traumatic brain injury; mitochondria; oxidative lipidomics; oxidative stress; autophagy
Date Deposited: 30 Jan 2012 19:32
Last Modified: 30 Jan 2017 06:15
URI: http://d-scholarship.pitt.edu/id/eprint/10837

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  • Neuronal Survival after Traumatic Brain Injury: Cardiolipin-a Critical Target. (deposited 30 Jan 2012 19:32) [Currently Displayed]

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