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While oxidative stress has traditionally been viewed as a precursor to cell death-mediated cognitive decline, cell death is absent in many patients and preclinical models with memory impairment. Here, we tested whether excessive mitochondrial reactive oxygen species (ROS) actively contribute to memory impairment through mechanisms distinct from cell death. Using Kv1.1 knockout (KO) mice, a TLE model with mitochondrial respiratory chain complex I (MRCI) impairment, we found elevated hippocampal mitochondrial superoxide, impaired recognition memory, deficits in synaptic plasticity, and abnormal sharp wave\u2013ripple oscillations. Applying the MRCI inhibitor rotenone to wild-type hippocampal slices caused increased superoxide and mirrored electrophysiology deficits. Both acute and sub-chronic treatment with the mitochondria-targeted antioxidant mitoquinone (MitoQ) reduced superoxide levels, rescued synaptic plasticity, restored network activity, and normalized memory performance in KO mice\u2014without altering seizure frequency, severity, or neuronal excitability. Our results identify mitochondrial superoxide as a reversible driver of hippocampal dysfunction in epilepsy and demonstrate that mitochondria-targeted antioxidant therapy can restore cognition despite persistent seizures. This study provides proof-of-concept for novel treatments improving cognitive comorbidities in TLE beyond seizure control.<\/jats:p>","DOI":"10.3390\/antiox15020259","type":"journal-article","created":{"date-parts":[[2026,2,18]],"date-time":"2026-02-18T09:22:46Z","timestamp":1771406566000},"page":"259","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Targeted Reduction of Excessive Mitochondrial Superoxide by Mitoquinone Rescues Cognitive Impairment Without Affecting Spontaneous Recurrent Seizures in a Mouse Model of Temporal Lobe Epilepsy"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7385-1293","authenticated-orcid":false,"given":"Segewkal H.","family":"Heruye","sequence":"first","affiliation":[{"name":"Department of Pharmacology & Neuroscience, School of Medicine, Creighton University, Omaha, NE 68174, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephanie A.","family":"Matthews","sequence":"additional","affiliation":[{"name":"Department of Pharmacology & Neuroscience, School of Medicine, Creighton University, Omaha, NE 68174, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7164-2495","authenticated-orcid":false,"given":"Shruthi H.","family":"Iyer","sequence":"additional","affiliation":[{"name":"Department of Pharmacology & Neuroscience, School of Medicine, Creighton University, Omaha, NE 68174, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1661-6518","authenticated-orcid":false,"given":"Malavika","family":"Deodhar","sequence":"additional","affiliation":[{"name":"Department of Pharmacology & Neuroscience, School of Medicine, Creighton University, Omaha, NE 68174, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8642-866X","authenticated-orcid":false,"given":"Ted J.","family":"Warren","sequence":"additional","affiliation":[{"name":"Department of Pharmacology & Neuroscience, School of Medicine, Creighton University, Omaha, NE 68174, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter J.","family":"West","sequence":"additional","affiliation":[{"name":"Department of Pharmacology & Toxicology, College of Pharmacy, University of Utah, Salt Lake City, UT 84112, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5072-3694","authenticated-orcid":false,"given":"Kristina A.","family":"Simeone","sequence":"additional","affiliation":[{"name":"Department of Pharmacology & Neuroscience, School of Medicine, Creighton University, Omaha, NE 68174, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8716-7211","authenticated-orcid":false,"given":"Timothy A.","family":"Simeone","sequence":"additional","affiliation":[{"name":"Department of Pharmacology & Neuroscience, School of Medicine, Creighton University, Omaha, NE 68174, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,18]]},"reference":[{"key":"ref_1","first-page":"821","article-title":"National and State Estimates of the Numbers of Adults and Children with Active Epilepsy\u2014United States, 2015","volume":"66","author":"Zack","year":"2017","journal-title":"MMWR"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/j.yebeh.2016.01.011","article-title":"Cognitive impairment in older adults with epilepsy: Characterization and risk factor analysis","volume":"56","author":"Miller","year":"2016","journal-title":"Epilepsy Behav."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Novak, A., Vizjak, K., and Rakusa, M. 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