Transgenic overexpression of adenine nucleotide translocase 1 protects ischemic hearts against oxidative stress
Abstract
Unlabelled Ischemia impairs the adenine nucleotide translocase (ANT), which transports ADP and ATP across the inner mitochondrial membrane. We investigated whether ANT1 overexpression has protective effects on ischemic hearts. Myocardial infarction was induced in wild-type (WT) and heart-specific ANT1-transgenic (ANT1-TG) rats, and hypoxia was set in isolated cardiomyocytes. ANT1 overexpression reduced the myocardial infarct area and increased the survival rate of infarcted rats. Reduced ANT1 expression and increased 4-hydroxynonenal modification of ANT paralleled to impaired ANT function in infarcted WT hearts. ANT1 overexpression improved ANT expression and function. This was accompanied by reduced mitochondrial cytochrome C release and caspase-3 activation. ANT1-TG hearts suffered less from oxidative stress, as shown by lower protein carbonylation and 4-hydroxynonenal modification of ANT. ANT1 overexpression also increased cell survival of hypoxic cardiomyocytes and attenuated reactive oxygen species (ROS) production. This was linked to higher stability of mitochondrial membrane potential and lower activity of ROS detoxifying catalase. ANT1-TG cardiomyocytes also showed higher resistance against H2O2 treatment, which was independent of catalase activity. In conclusion, ANT1 overexpression compensates impaired ANT activity under oxygen-restricted conditions. It reduces ROS production and oxidative stress, stabilizes mitochondrial integrity, and increases survival, making ANT1 a component in ROS management and heart protection during ischemia.Key messages ANT1 overexpression reduces infarct size and increases survival after infarction. ANT1 overexpression compensates restricted ANT expression and function in infarcted hearts. Increased ANT1 expression enhances mitochondrial integrity. ANT1-overexpressing hearts reduce oxidative stress by decreasing ROS generation. ANT1 is a component in ROS management and heart protection.
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UCP3 expression in cultured myotubes and rodent skeletal muscle has been linked to modulation of fatty acid oxidation, mitochondrial integrity, and management of ROS/oxidative stress.
“its expression in cultured myotubes and rodent skeletal muscle has been linked to modulation of fatty acid oxidation [56–58], mitochondrial integrity, and to management of ROS/oxidative stress [59–62].”
From Proinflammatory NFkB signalling promotes mitochondrial dysfunction in skeletal muscle in response to cellular fuel overloading (2019) · cites this paper as [62]
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- Authors
- Klumpe, I., Savvatis, K., Westermann, D., Tschöpe, C., Rauch, U., Landmesser, U., Schultheiss, H.-P., & Dörner, A.
- Affiliations
- Freie Universität Berlin (DE)
- Berlin-Brandenburger Centrum für Regenerative Therapien (DE)
- Universität Hamburg (DE)
- Charité – Universitätsmedizin Berlin (DE)
- Stiftung Charité (DE)
- Corresponding author
- Dörner, Andrea
- ORCID
- Venue
- Journal of Molecular Medicine
- Published
- 2016-04-15
- Volume
- 94
- Issue
- 6
- Pages
- 645-653
- ISSN
- 0946-2716 (ISSN-L)
- 1432-1440
- OpenAlex
- W2338941232
- Cited by
- 35
- References
- 34
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 2 · 2023: 5 · 2022: 3 · 2021: 5 · 2020: 2 · 2019: 6 · 2018: 1 · 2017: 4 · 2016: 2
- FWCI
- 3.94
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Journal of Molecular Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Deutsche Forschungsgemeinschaft (Transregio 19, C7)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Cardiac Ischemia and Reperfusion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- myocardial ischemia, myocardial infarction, oxidative stress, reactive oxygen species, 4-hydroxynonenal, cytochrome c release, caspase-3 activation, cardiomyocyte hypoxia, mitochondrial membrane potential, catalase, cardioprotection
- MeSH terms
- Aldehydes, Animals, Catalase, Cell Survival, Gene Expression Regulation, Hydrogen Peroxide, Male, Mitochondria, Heart, Myocardial Infarction, Signal Transduction, Cell Hypoxia, Survival Analysis, Reactive Oxygen Species, Oxidative Stress, Myocytes, Cardiac, Adenine Nucleotide Translocator 1, Cytochromes c, Protein Carbonylation, Rats, Membrane Potential, Mitochondrial, Caspase 3, Rats, Transgenic, Primary Cell Culture
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