Mitochondria control critical cell functions that can impact epilepsy and its comorbidities. Key features of temporal lobe epilepsy (TLE) such as its progressive nature, rising incidence with aging and bioenergetic demands suggest mitochondrial involvement. Mitochondrial dysfunction has been implicated in various neurological diseases including experimental models of TLE. However, the precise mechanisms underlying mitochondrial dysfunction in TLE remain unclear. The proposal builds upon our previous discoveries of impaired mitochondrial redox status and bioenergetics in experimental models of TLE. A central mediator that links mitochondrial oxidative stress with bionenergetic dysfunction is sirtuin-3 (SIRT3), a mitochondrial nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase known to maintain metabolic homeostasis. SIRT3 is exquisitely sensitive to aging and serves as a major switch to regulate mitochondrial protein acetylation to control metabolic flux and energy. It is hypothesized that decreased SIRT3 activity and consequent increases in mitochondrial protein acetylation contribute to the impaired bioenergetics in TLE. Using novel mass spectrometry-based quantitative mitochondrial acetylomics, brain-specific SIRT3 conditional knockout mice and restorative therapies, we plan to explore the role of SIRT3 in TLE.
Aim 1 will determine if SIRT3 dysfunction occurs following chemoconvulsant-induced epilepsy.
Aim 2 will determine if conditional deletion of SIRT3 or its target, Sod2 is sufficient to cause age-related epilepsy and cognitive dysfunction and Aim 3 will determine if restoration of SIRT3 activity by supplementation with NAD+ precursor attenuates deficits observed in chemoconvulsant-induced TLE. Collectively, this project can identify a novel role of SIRT3 as a mediator of mitochondrial dysfunction in chronic seizures and/or cognitive impairment associated with TLE and provide a therapeutic approach for its treatment.

Public Health Relevance

The proposed research will provide novel insight into malfunction of energy producing pathways in epilepsy and suggest innovative metabolic treatments for controlling seizures and related memory impairment.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
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Whittemore, Vicky R
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University of Colorado Denver
Schools of Pharmacy
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Pearson-Smith, Jennifer N; Liang, Li-Ping; Rowley, Shane D et al. (2017) Oxidative Stress Contributes to Status Epilepticus Associated Mortality. Neurochem Res 42:2024-2032
Pearson-Smith, Jennifer N; Patel, Manisha (2017) Metabolic Dysfunction and Oxidative Stress in Epilepsy. Int J Mol Sci 18:
McElroy, Pallavi B; Liang, Li-Ping; Day, Brian J et al. (2017) Scavenging reactive oxygen species inhibits status epilepticus-induced neuroinflammation. Exp Neurol 298:13-22
McElroy, Pallavi B; Sri Hari, Ashwini; Day, Brian J et al. (2017) Post-translational Activation of Glutamate Cysteine Ligase with Dimercaprol: A NOVEL MECHANISM OF INHIBITING NEUROINFLAMMATION IN VITRO. J Biol Chem 292:5532-5545
Heischmann, Svenja; Quinn, Kevin; Cruickshank-Quinn, Charmion et al. (2016) Exploratory Metabolomics Profiling in the Kainic Acid Rat Model Reveals Depletion of 25-Hydroxyvitamin D3 during Epileptogenesis. Sci Rep 6:31424
Pearson, Jennifer N; Patel, Manisha (2016) The role of oxidative stress in organophosphate and nerve agent toxicity. Ann N Y Acad Sci 1378:17-24
Walker, Lauren E; Janigro, Damir; Heinemann, Uwe et al. (2016) WONOEP appraisal: Molecular and cellular biomarkers for epilepsy. Epilepsia 57:1354-62
Liang, Li-Ping; Patel, Manisha (2016) Plasma cysteine/cystine redox couple disruption in animal models of temporal lobe epilepsy. Redox Biol 9:45-49
Patel, Manisha (2016) Targeting Oxidative Stress in Central Nervous System Disorders. Trends Pharmacol Sci 37:768-78
Kumar, Maneesh G; Rowley, Shane; Fulton, Ruth et al. (2016) Altered Glycolysis and Mitochondrial Respiration in a Zebrafish Model of Dravet Syndrome. eNeuro 3:

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