{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,9]],"date-time":"2025-12-09T06:17:14Z","timestamp":1765261034998,"version":"3.46.0"},"reference-count":54,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2025,12,6]],"date-time":"2025-12-06T00:00:00Z","timestamp":1764979200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["SC1NS127764","5U54MD007600","T32GM148406"],"award-info":[{"award-number":["SC1NS127764","5U54MD007600","T32GM148406"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Mitochondrial dysfunction and loss of mitochondrial DNA (mtDNA) integrity are increasingly recognized as key contributors to liver diseases such as cirrhosis and hepatocellular carcinoma. However, the role of mtDNA repair in maintaining mitochondrial homeostasis during liver injury remains poorly understood. Apurinic\/apyrimidinic endonuclease 1 (APE1), encoded by the Apex1 gene, is the primary endonuclease mediating base excision repair of mtDNA. We hypothesize that APE1 is required to preserve mtDNA integrity in response to genotoxic stress in the liver. To test this, wild-type (WT) and Apex1 haploinsufficient mice (Apex1+\/\u2212) were treated with the alkylating agent azoxymethane (AOM), a carcinogen bioactivated in the liver, and tissues were collected 20 weeks after the last exposure. Apex1+\/\u2212 mice exhibited a 3.2-fold increase in mtDNA lesions and a 55% reduction in mtDNA abundance, changes not observed in WT mice. Bioenergetics profiling revealed a 1.5-fold increase in the ATP5\u03b2\/GAPDH ratio in WT mice and a 2.5-fold increase in Apex1+\/\u2212 mice, indicating a more pronounced shift toward oxidative phosphorylation in the absence of full APE1 function. Histological analysis indicated increased nuclear inclusions and ductular proliferation in both strains, whereas fibrosis was attenuated in Apex1+\/\u2212 mice. Collectively, these findings show that APE1 is essential for preserving mtDNA integrity and regulating bioenergetics and histopathological responses to alkylation-induced liver injury, highlighting its dual role in mitochondrial maintenance and modulating inflammatory outcomes.<\/jats:p>","DOI":"10.3390\/biom15121706","type":"journal-article","created":{"date-parts":[[2025,12,8]],"date-time":"2025-12-08T08:21:43Z","timestamp":1765182103000},"page":"1706","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Mitochondrial DNA Damage and Histological Features in Liver Tissue of Azoxymethane-Treated Apex1 Haploinsufficient Mice"],"prefix":"10.3390","volume":"15","author":[{"given":"Carmen M.","family":"P\u00e9rez-P\u00e9rez","sequence":"first","affiliation":[{"name":"Department of Physiology, University of Puerto Rico Medical Sciences Campus, San Juan, PR 00936, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adlin","family":"Rodr\u00edguez-Mu\u00f1oz","sequence":"additional","affiliation":[{"name":"Department of Physiology, University of Puerto Rico Medical Sciences Campus, San Juan, PR 00936, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6460-7165","authenticated-orcid":false,"given":"Gerardo G.","family":"Mackenzie","sequence":"additional","affiliation":[{"name":"Department of Nutrition, University of California Davis, Davis, CA 95616, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karen E.","family":"Matsukuma","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, University of California Davis, Davis, CA 95616, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mar\u00eda R.","family":"Castro-Achi","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, University of Puerto Rico Medical Sciences Campus, San Juan, PR 00936, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sylvette","family":"Ayala-Pe\u00f1a","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, University of Puerto Rico Medical Sciences Campus, San Juan, PR 00936, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4792-1451","authenticated-orcid":false,"given":"Carlos A.","family":"Torres-Ramos","sequence":"additional","affiliation":[{"name":"Department of Physiology, University of Puerto Rico Medical Sciences Campus, San Juan, PR 00936, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Auger, C., Alhasawi, A., Contavadoo, M., and Appanna, V.D. 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