Inhibition of NADH-Linked Mitochondrial Respiration by 4-Hydroxy-2-nonenal
Abstract
During the progression of certain degenerative conditions, including myocardial ischemia-reperfusion injury, mitochondria are a source of increased free-radical generation and exhibit declines in respiratory function(s). It has therefore been suggested that oxidative damage to mitochondrial components plays a critical role in the pathology of these processes. Polyunsaturated fatty acids of membrane lipids are prime molecular targets of free-radical damage. A major product of lipid peroxidation, 4-hydroxy-2-nonenal (HNE), is highly cytotoxic and can readily react with and damage protein. In this study, the effects of HNE on intact cardiac mitochondria were investigated to gain insight into potential mechanisms by which free radicals mediate mitochondrial dysfunction. Exposure of mitochondria to micromolar concentrations of HNE caused rapid declines in NADH-linked but not succinate-linked state 3 and uncoupled respiration. The activity of complex I was unaffected by HNE under the conditions of our experiments. Loss of respiratory activity reflected the inability of HNE-treated mitochondria to meet NADH demand during maximum rates of O2 consumption. HNE exerted its effects on intact mitochondria by inactivating alpha-ketoglutarate dehydrogenase. These results therefore identify a potentially important mechanism by which free radicals bring about declines in mitochondrial respiration.
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Ion-channel function is subject to modification by thiol reducing and oxidizing agents.
“Ion-channel function is also subject to modification by thiol reducing and oxidizing agents (73, 163, 164).”
From Mitochondrial reactive oxygen species production in excitable cells: Modulators of mitochondrial and cell function (2009) · cites this paper as [163]
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- Authors
- Humphries, K. M., Yoo, Y., & Szweda, L. I.
- Affiliations
- Case Western Reserve University (US)
- Venue
- Biochemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 1998-01-01
- Volume
- 37
- Issue
- 2
- Pages
- 552-557
- ISSN
- 0006-2960 (ISSN-L)
- 1520-4995
- OpenAlex
- W2059545411
- Cited by
- 231
- References
- 22
- Citations by year
- 2026: 5 · 2025: 4 · 2023: 4 · 2022: 4 · 2021: 6 · 2020: 5 · 2019: 5 · 2018: 4 · 2017: 4 · 2016: 10 · 2015: 4 · 2014: 3 · 2013: 7 · 2012: 11
- FWCI
- 3.72
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biochemistry (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Health Sciences › Medicine › Biochemistry › Antioxidant Activity and Oxidative Stress
- Keywords
- 4-hydroxynonenal, lipid peroxidation, mitochondrial respiration, alpha-ketoglutarate dehydrogenase, free radicals, oxidative damage, myocardial ischemia-reperfusion injury, heart mitochondria, complex I, uncoupled respiration
- MeSH terms
- Aldehydes, Animals, Glutamate Dehydrogenase, Ketoglutarate Dehydrogenase Complex, Mitochondria, Heart, NAD, Oxygen Consumption, Sarcolemma, Uncoupling Agents, Lipid Peroxidation, NAD(P)H Dehydrogenase (Quinone), Rats, Sprague-Dawley, Cell Respiration, Rats
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