Ischemic defects in the electron transport chain increase the production of reactive oxygen species from isolated rat heart mitochondria
Abstract
Cardiac ischemia decreases complex III activity, cytochrome c content, and respiration through cytochrome oxidase in subsarcolemmal mitochondria (SSM) and interfibrillar mitochondria (IFM). The reversible blockade of electron transport with amobarbital during ischemia protects mitochondrial respiration and decreases myocardial injury during reperfusion. These findings support that mitochondrial damage occurs during ischemia and contributes to myocardial injury during reperfusion. The current study addressed whether ischemic damage to the electron transport chain (ETC) increased the net production of reactive oxygen species (ROS) from mitochondria. SSM and IFM were isolated from 6-mo-old Fisher 344 rat hearts following 25 min global ischemia or following 40 min of perfusion alone as controls. H 2 O 2 release from SSM and IFM was measured using the amplex red assay. With glutamate as a complex I substrate, the net production of H 2 O 2 was increased by 178 ± 14% and 179 ± 17% in SSM and IFM ( n = 9), respectively, following ischemia compared with controls ( n = 8). With succinate as substrate in the presence of rotenone, H 2 O 2 increased by 272 ± 22% and 171 ± 21% in SSM and IFM, respectively, after ischemia. Inhibitors of electron transport were used to assess maximal ROS production. Inhibition of complex I with rotenone increased H 2 O 2 production by 179 ± 24% and 155 ± 14% in SSM and IFM, respectively, following ischemia. Ischemia also increased the antimycin A-stimulated production of H 2 O 2 from complex III. Thus ischemic damage to the ETC increased both the capacity and the net production of H 2 O 2 from complex I and complex III and sets the stage for an increase in ROS production during reperfusion as a mechanism of cardiac injury.
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A physiologic response to low O2 requires an O2 sensor coupled to a signal-transduction system.
“A physiologic response to low O2 requires an O2 sensor coupled to a signal-transduction system (80).”
From Mitochondrial reactive oxygen species production in excitable cells: Modulators of mitochondrial and cell function (2009) · cites this paper as [80]
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- Authors
- Chen, Q., Moghaddas, S., Hoppel, C. L., & Lesnefsky, E. J.
- Affiliations
- Case Western Reserve University (US)
- Case Comprehensive Cancer Center (US)
- United States Department of Veterans Affairs (US)
- Venue
- American Journal of Physiology-Cell Physiology
- Publisher
- American Physiological Society
- Published
- 2008-02
- Volume
- 294
- Issue
- 2
- Pages
- C460-C466
- ISSN
- 0363-6143 (ISSN-L)
- 1522-1563
- OpenAlex
- W2169052274
- Cited by
- 299
- References
- 61
- Citations by year
- 2026: 4 · 2025: 9 · 2024: 7 · 2023: 5 · 2022: 12 · 2021: 15 · 2020: 13 · 2019: 12 · 2018: 12 · 2017: 19 · 2016: 14 · 2015: 23 · 2014: 32 · 2013: 30 · 2012: 25
- FWCI
- 9.68
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- American Journal of Physiology-Cell Physiology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Veterans Affairs
- Office of Research and Development
- National Institutes of Health
- National Institute on Aging (2P01 AG 15885, P01AG015885)
- 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
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Keywords
- myocardial ischemia, electron transport chain, reactive oxygen species, hydrogen peroxide production, mitochondrial respiration, complex I, cytochrome bc1 complex, subsarcolemmal mitochondria, interfibrillar mitochondria, myocardial ischemia-reperfusion injury, amobarbital, rotenone, antimycin A, glutamate, succinic acid, cytochrome c, cytochrome c oxidase
- MeSH terms
- Animals, Electron Transport, Hydrogen Peroxide, Male, Mitochondria, Heart, Myocardium, Protein Synthesis Inhibitors, Rats, Inbred F344, Rotenone, Electron Transport Complex III, Uncoupling Agents, Reperfusion Injury, Myocardial Ischemia, Reactive Oxygen Species, Oxidative Stress, Glutamic Acid, Ischemic Preconditioning, Succinic Acid, Electron Transport Complex I, Electron Transport Chain Complex Proteins, Rats
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