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Biomolecules
Volume 15
Issue 12
10.3390/biom15121706
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This is an early access version, the complete PDF, HTML, and XML versions will be available soon.
Article

Mitochondrial DNA Damage and Histological Features in Liver Tissue of Azoxymethane-Treated Apex1 Haploinsufficient Mice

by
Carmen M. Pérez-Pérez
1,
Adlin Rodríguez-Muñoz
1,
Gerardo G. Mackenzie
2,
Karen E. Matsukuma
3,
María R. Castro-Achi
4,
Sylvette Ayala-Peña
4 and
Carlos A. Torres-Ramos
1,*
1
Department of Physiology, University of Puerto Rico Medical Sciences Campus, San Juan, PR 00936, USA
2
Department of Nutrition, University of California Davis, Davis, CA 95616, USA
3
Department of Pathology and Laboratory Medicine, University of California Davis, Davis, CA 95616, USA
4
Department of Pharmacology and Toxicology, University of Puerto Rico Medical Sciences Campus, San Juan, PR 00936, USA
*
Author to whom correspondence should be addressed.
Biomolecules 2025, 15(12), 1706; https://doi.org/10.3390/biom15121706 (registering DOI)
Submission received: 7 October 2025 / Revised: 14 November 2025 / Accepted: 26 November 2025 / Published: 6 December 2025
(This article belongs to the Special Issue Functional Analysis of Genes Related to DNA Damage)
Versions Notes

Abstract

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+/−) 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+/− 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 ATP5β/GAPDH ratio in WT mice and a 2.5-fold increase in Apex1+/− 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+/− 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.
Keywords: mitochondria; base excision repair; liver mitochondria; base excision repair; liver

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MDPI and ACS Style

Pérez-Pérez, C.M.; Rodríguez-Muñoz, A.; Mackenzie, G.G.; Matsukuma, K.E.; Castro-Achi, M.R.; Ayala-Peña, S.; Torres-Ramos, C.A. Mitochondrial DNA Damage and Histological Features in Liver Tissue of Azoxymethane-Treated Apex1 Haploinsufficient Mice. Biomolecules 2025, 15, 1706. https://doi.org/10.3390/biom15121706

AMA Style

Pérez-Pérez CM, Rodríguez-Muñoz A, Mackenzie GG, Matsukuma KE, Castro-Achi MR, Ayala-Peña S, Torres-Ramos CA. Mitochondrial DNA Damage and Histological Features in Liver Tissue of Azoxymethane-Treated Apex1 Haploinsufficient Mice. Biomolecules. 2025; 15(12):1706. https://doi.org/10.3390/biom15121706

Chicago/Turabian Style

Pérez-Pérez, Carmen M., Adlin Rodríguez-Muñoz, Gerardo G. Mackenzie, Karen E. Matsukuma, María R. Castro-Achi, Sylvette Ayala-Peña, and Carlos A. Torres-Ramos. 2025. "Mitochondrial DNA Damage and Histological Features in Liver Tissue of Azoxymethane-Treated Apex1 Haploinsufficient Mice" Biomolecules 15, no. 12: 1706. https://doi.org/10.3390/biom15121706

APA Style

Pérez-Pérez, C. M., Rodríguez-Muñoz, A., Mackenzie, G. G., Matsukuma, K. E., Castro-Achi, M. R., Ayala-Peña, S., & Torres-Ramos, C. A. (2025). Mitochondrial DNA Damage and Histological Features in Liver Tissue of Azoxymethane-Treated Apex1 Haploinsufficient Mice. Biomolecules, 15(12), 1706. https://doi.org/10.3390/biom15121706

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