Mitochondrial Sirtuin-3 dysregulation in epileptogenesis

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 DESCRIPTION (provided by applicant): 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.