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Bioenergetic failure is a primary mechanism for cellular dysfunction. We used the mitochondrial activator humanin (HN) to try to normalize the disruptive action of TBI on cellular bioenergetics in the hippocampus. We found that HN supplied right after the injury counteracted the action of TBI on metabolic sensing proteins (LKB1, AMPK, and AKT). HN also counteracted cognitive function and restored the synaptic proteins (Synapsin I and PSD-95) at three weeks post-injury. Moreover, HN normalized the disruptive action of TBI on mitochondrial functioning and dynamics (fusion, fission, and mitophagy). In addition, HN treatment counteracted TBI\u2019s effects on mitochondrial biogenesis (PGC-1\u03b1), antioxidant (SOD2), and apoptotic marker (CC3). Furthermore, HN intervention in injured animals counteracted the gene expression linked with inflammation (Itgax, SALL1, GFAP, and NLRP3), synaptic plasticity (HDAC2), and bioenergetics (mtND2, TFAM, SIRT1, and SIRT3). These observations emphasize the therapeutic potential of HN by normalizing the fundamental aspects of TBI pathogenesis central to cellular bioenergetics and synaptic plasticity.<\/jats:p>","DOI":"10.3390\/biom15121705","type":"journal-article","created":{"date-parts":[[2025,12,8]],"date-time":"2025-12-08T08:21:43Z","timestamp":1765182103000},"page":"1705","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Enduring Effects of Humanin on Mitochondrial Systems in TBI Pathology"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9194-3415","authenticated-orcid":false,"given":"Pavan","family":"Thapak","sequence":"first","affiliation":[{"name":"Department of Integrative Biology and Physiology, University of California Los Angeles, Los Angeles, CA 90095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhe","family":"Ying","sequence":"additional","affiliation":[{"name":"Department of Integrative Biology and Physiology, University of California Los Angeles, Los Angeles, CA 90095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2535-6180","authenticated-orcid":false,"given":"Fernando","family":"Gomez-Pinilla","sequence":"additional","affiliation":[{"name":"Department of Integrative Biology and Physiology, University of California Los Angeles, Los Angeles, CA 90095, USA"},{"name":"Department of Neurosurgery, University of California Los Angeles, Los Angeles, CA 90095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"107389","DOI":"10.1016\/j.phrs.2024.107389","article-title":"The Bioenergetics of Traumatic Brain Injury and Its Long-Term Impact for Brain Plasticity and Function","volume":"208","author":"Thapak","year":"2024","journal-title":"Pharmacol. 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