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Dependence of H2O2 Formation by Rat Heart Mitochondria on Substrate Availability and Donor Age
Abstract
We have examined the substrate specificity and inhibitor sensitivity of H2O2 formation by rat heart mitochondria. Active H2O2 production requires both a high fractional reduction of Complex I (indexed by NADH/NAD+ + NADH ratio) and a high membrane potential, delta psi. These conditions are achieved with supraphysiological concentrations of succinate. With physiological concentrations of NAD-linked substrates, rates of H2O2 formation are much lower (less than 0.1% of respiratory chain electron flux) but may be stimulated by the Complex III inhibitor antimycin A, but not by myxothiazol. Addition of Mn2+ to give 10 nmol/mg of mitochondrial protein enhances H2O2 production with all substrate combinations, possibly by repleting mitochondrial superoxide dismutase with this cation. Contrary to previously published work, no increased activity of H2O2 production was found with heart mitochondria from senescent (24 month) rats, relative to young adults (6 month).
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“Δψm is an important factor for maintaining cellular energy homeostasis, and small reductions in Δψm induced by mild uncoupling were shown to decrease H2O2 emissions (51,52) and produce a natural antioxidant effect (53).”
From TFAM Enhances Fat Oxidation and Attenuates High-Fat Diet–Induced Insulin Resistance in Skeletal Muscle (2019) · cites this paper as [51]
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BackgroundInfluentialMitochondria and ageing: Role in heart, skeletal muscle and adipose tissue
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Park, J., Lee, J., & Choi, C. (2011) · PLoS ONE · doi:10.1371/journal.pone.0023211 · Cited by 241
“Maximum electron leaking in oxidative condition 20% per time step estimated from [25,26]”
BackgroundCocco, T., Di, M., Papa, P., & Lorusso, M. P. (1999) · Free Radical Biology and Medicine · doi:10.1016/s0891-5849(99)00034-9 · Cited by 228
Regulation of hydrogen peroxide production by brain mitochondria by calcium and Bax
Starkov, A. A., Polster, B. M., & Fiskum, G. M. (2002) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2002.01153.x · Cited by 227
“…finding verifies the contribution of rotenone-sensitive reversed electron flow through Complex I as a major site of ROS production supported by succinate (Hinkle et al. 1967; Hansford et al. 1997; Korshunov et al. 1997; Turrens 1997; Lass et al. 1998; Votyakova and Reynolds 2001; Liu et al. 2002).”
BackgroundPicard, M., Hepple, R. T., & Burelle, Y. (2012) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00368.2011 · Cited by 214
Role of redox metabolism for adaptation of aquatic animals to drastic changes in oxygen availability
Welker, A. F., Moreira, D. C., Campos, E. G., & Hermes‐Lima, M. (2013) · Comparative Biochemistry and Physiology Part A Molecular & Integrative Physiology · doi:10.1016/j.cbpa.2013.04.003 · Cited by 219
“These substrates provide electrons to the respiratory chain, increasing the mitochondrial inner membrane potential (ΔΨ), which promotes the generation of ROS (Section 2.4; Hansford et al., 1997; Murphy, 2009).”
BackgroundMethodInfluentialTreberg, J. R., Quinlan, C. L., & Brand, M. D. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.252502 · Cited by 212
Han, D., Canali, R., Rettori, D., & Kaplowitz, N. (2003) · Molecular Pharmacology · doi:10.1124/mol.64.5.1136 · Cited by 211
“The mechanism of H2O2 production by mitochondria, on the other hand, has been extensively studied both in physiological and pathological situations such as aging (Chance et al., 1979; Cadenas and Boveris, 1980; Turrens et al., 1985; Hansford et al., 1997).”
BackgroundMitochondrial Aging: Open Questionsa
Beckman, K. B., & Ames, B. N. (1998) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.1998.tb09897.x · Cited by 211
“represents only one of numerous pro- and antioxidant mechanisms whose modulation could accelerate or retard aging, a point that has recently been made by others.(23) Last,”
InfluentialOxidative stress and mitochondrial function with aging – the effects of calorie restriction
Merry, B. J. (2003) · Aging Cell · doi:10.1046/j.1474-9728.2003.00074.x · Cited by 207
“Whether mitochondrial oxidant production increases with age is still unclear because there is a lack of agreement between published studies (Guarnieri et al ., 1992; Nohl, 1993; Rollo et al ., 1996; Hansford et al ., 1997; Kwong & Sohal, 1998).”
ResultD-beta-hydroxybutyrate extends lifespan in C. elegans
Edwards, C., Canfield, J., Copes, N., Rehan, M., Lipps, D., & Bradshaw, P. C. (2014) · Aging · doi:10.18632/aging.100683 · Cited by 211
“15% of electrons passing through the mitochondrial electron transport chain (ETC) combine with molecular oxygen to form superoxide [7, 8].”
Barja, G., & Herrero, A. (1998) · Journal of Bioenergetics and Biomembranes · doi:10.1023/a:1020592719405 · Cited by 203
Mitochondrial Complex I: Structural and functional aspects
Lenaz, G., Fato, R., Genova, M. L., Bergamini, C., Bianchi, C., & Biondi, A. (2006) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2006.05.007 · Cited by 207
“Reverse electron transfer-supported ROS production requires high membrane potential and is inhibited by uncouplers and by processes dissipating membrane potential [108–111].”
BackgroundAon, M. A., Stanley, B. A., Sivakumaran, V., Kembro, J. M., O'Rourke, B., Paolocci, N., & Cortassa, S. (2012) · Journal of General Physiology · doi:10.1085/jgp.201210772 · Cited by 200
“ND Hansford et al., 1997 ndet ND St-Pierre et al., 2002 0.105 0.08 0.3–0.04 This study Pigeon 0.3–0.6 ND 2–”
InfluentialMiller, V. J., Villamena, F. A., & Volek, J. S. (2018) · Journal of Nutrition and Metabolism · doi:10.1155/2018/5157645 · Cited by 204
Is there more to aging than mitochondrial DNA and reactive oxygen species?
ALEXEYEV, M. F. (2009) · FEBS Journal · doi:10.1111/j.1742-4658.2009.07269.x · Cited by 196
“[26] who found that active H2O2 production, which is an indirect measure of superoxide (O2) generation, requires both a high fractional reduction of complex I, as determined by NADH/(NADH + NAD+) ratio, and a high membrane potential (ΔΨ).”
BackgroundMüller, F. L. (2000) · AGE · doi:10.1007/s11357-000-0022-9 · Cited by 203
“This may be due to the fact that when excess Complex II linked substrates are provided, reverseelectron transfer can occur through Complex I (66).”
BackgroundMethodInfluentialThyroid Hormone Effects on Mitochondrial Energetics
Harper, M.-E., & Seifert, E. L. (2008) · Thyroid · doi:10.1089/thy.2007.0250 · Cited by 194
Brennan, L., & Kantorow, M. (2008) · Experimental Eye Research · doi:10.1016/j.exer.2008.05.018 · Cited by 197
Measuring mitochondrial reactive oxygen species
Esposti, M. D. (2002) · Methods · doi:10.1016/s1046-2023(02)00039-7 · Cited by 192
Metadata
- Authors
- Hansford, R. G., Hogue, B. A., & Mildaziene, V.
- Affiliations
- National Institute on Aging (US)
- Venue
- Journal of Bioenergetics and Biomembranes
- Published
- 1997-02
- Volume
- 29
- Issue
- 1
- Pages
- 89-95
- ISSN
- 0145-479X (ISSN-L)
- 1573-6881
- OpenAlex
- W2414123687
- Cited by
- 447
- References
- 26
- Citations by year
- 2026: 4 · 2025: 7 · 2024: 9 · 2023: 2 · 2022: 12 · 2021: 11 · 2020: 10 · 2019: 15 · 2018: 13 · 2017: 11 · 2016: 11 · 2015: 11 · 2014: 26 · 2013: 17 · 2012: 28
- FWCI
- 5.10
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Journal of Bioenergetics and Biomembranes (publishedVersion)
- PubMed (publishedVersion)
- Lithuanian University of Health Sciences (submittedVersion)
- 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 › Physiology (medical) › Nitric Oxide and Endothelin Effects
- Keywords
- hydrogen peroxide production, heart mitochondria, mitochondrial reactive oxygen species, complex I, NAD+/NADH ratio, membrane potential, succinic acid, antimycin A, myxothiazol, manganese, superoxide dismutase, donor age, senescence, substrate specificity, inhibitor sensitivity
- MeSH terms
- Aging, Animals, Electron Transport, Hydrogen Peroxide, Mitochondria, Heart, Substrate Specificity, Succinates, Uncoupling Agents, Rats
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