Ambivalent effects of diazoxide on mitochondrial ROS production at respiratory chain complexes I and III
Abstract
Background Reactive oxygen species (ROS) are among the main determinants of cellular damage during ischemia and reperfusion. There is also ample evidence that mitochondrial ROS production is involved in signaling during ischemic and pharmacological preconditioning. In a previous study we analyzed the mitochondrial effects of the efficient preconditioning drug diazoxide and found that it increased the mitochondrial oxidation of the ROS-sensitive fluorescent dye 2',7'-dichlorodihydrofluorescein (H(2)DCF) but had no direct impact on the H(2)O(2) production of submitochondrial particles (SMP) or intact rat heart mitochondria (RHM).Methods H(2)O(2) generation of bovine SMP and tightly coupled RHM was monitored under different conditions using the amplex red/horseradish peroxidase assay in response to diazoxide and a number of inhibitors.Results We show that diazoxide reduces ROS production by mitochondrial complex I under conditions of reverse electron transfer in tightly coupled RHM, but stimulates mitochondrial ROS production at the Q(o) site of complex III under conditions of oxidant-induced reduction; this stimulation is greatly enhanced by uncoupling. These opposing effects can both be explained by inhibition of complex II by diazoxide. 5-Hydroxydecanoate had no effect, and the results were essentially identical in the presence of Na(+) or K(+) excluding a role for putative mitochondrial K(ATP)-channels.General significance A straightforward rationale is presented to mechanistically explain the ambivalent effects of diazoxide reported in the literature. Depending on the metabolic state and the membrane potential of mitochondria, diazoxide-mediated inhibition of complex II promotes transient generation of signaling ROS at complex III (during preconditioning) or attenuates the production of deleterious ROS at complex I (during ischemia and reperfusion).
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Complex II activity can strongly influence ROS production by complexes I and III.
“Furthermore, it is well known that complex II activity can have major impact on the ROS production by complexes I and III [15,16].”
From Differential effects of complex II on mitochondrial ROS production and their relation to cardioprotective pre- and postconditioning (2013) · cites this paper as [15]
Complex II inhibitors have ambivalent effects on mitochondrial ROS production that depend on substrate supply, membrane potential, and the overall activities of respiratory chain and TCA cycle enzymes.
“Hence, it is not surprising that complex II inhibitors show ambivalent effects on mitochondrial ROS production [15,16] depending on substrate supply, membrane potential and overall activities of respiratory chain and TCA cycle enzymes.”
From Differential effects of complex II on mitochondrial ROS production and their relation to cardioprotective pre- and postconditioning (2013) · cites this paper as [15]
The protective effects of complex II inhibitors can be explained by their differential effects on complex I and complex III ROS production: they reduce complex I reverse-electron-transfer ROS during reperfusion and promote Qo-site complex III ROS by shifting the Q-pool to an intermediate redox state.
“The protective effects of complex II inhibitors could then be explained by their differential effects on complex I and complex III related ROS production: they reduce ROS that are generated at complex I by reverse electron transfer (RET) during reperfusion while they promote production of ROS at the Q o site of complex III by shifting the redox state of the Q-pool to an intermediate state [15].”
From Differential effects of complex II on mitochondrial ROS production and their relation to cardioprotective pre- and postconditioning (2013) · cites this paper as [15]
Under conditions of reverse electron transfer, inhibiting complex II lowers complex I-related ROS generation.
“Under these conditions inhibition of complex II leads to a reduction of complex I related ROS generation [15,16,19,20,24].”
From Differential effects of complex II on mitochondrial ROS production and their relation to cardioprotective pre- and postconditioning (2013) · cites this paper as [15]
Under very specific conditions, complex II can modulate superoxide production at the Qo site of complex III.
“Under very specific conditions, complex II can also modulate the superoxide production at the Q o site of complex III [15,16,33] (Fig. 3B).”
From Differential effects of complex II on mitochondrial ROS production and their relation to cardioprotective pre- and postconditioning (2013) · cites this paper as [15]
Complex II is recognized as a modulator of superoxide production by other mitochondrial enzymes, especially complexes I and III.
“Apart from the direct generation of ROS (Section 3.1), complex II has been recognized as a modulator of the superoxide production by other mitochondrial enzymes, especially the respiratory chain complexes I and III [15,16,25] that are generally regarded as main ROS sources in the mitochondria [3][4][5][6].”
From Differential effects of complex II on mitochondrial ROS production and their relation to cardioprotective pre- and postconditioning (2013) · cites this paper as [15]
Complex II inhibitors that bind the dicarboxylate site or the Qp site attenuate ROS production when succinate is the prevalent substrate.
“The ROS production is also attenuated by complex II inhibitors that bind either to the dicarboxylate site or the Qp site if succinate is the prevalent substrate [15,16,19,20,24].”
From Differential effects of complex II on mitochondrial ROS production and their relation to cardioprotective pre- and postconditioning (2013) · cites this paper as [15]
This mechanism is supported by several studies with isolated mitochondria.
“Such a mechanism is supported by several studies with isolated mitochondria [15,16,19,20,24].”
From Differential effects of complex II on mitochondrial ROS production and their relation to cardioprotective pre- and postconditioning (2013) · cites this paper as [15]
In isolated rat heart mitochondria, complex II inhibitors increase superoxide production at the Qo site of complex III only under specific conditions: succinate is the predominant substrate and oxidant-induced reduction occurs.
“In isolated rat heart mitochondria, complex II inhibitors can increase the superoxide production at the Q o site of complex III only under the specific conditions indicated in Section 3.2 and Fig. 3B [15,16,33], i.e. when succinate is the predominant substrate and under conditions of 'oxidant-induced reduction'.”
From Differential effects of complex II on mitochondrial ROS production and their relation to cardioprotective pre- and postconditioning (2013) · cites this paper as [15]
Similar atpenin A5 concentrations stimulated superoxide production at the Qo site of antimycin A-inhibited complex III, which may represent the source of signaling ROS during ischemic and pharmacological preconditioning.
“In addition, similar atpenin A5 concentrations stimulated the superoxide production at the Q o site of antimycin A inhibited complex III, which may represent the source of 'signaling ROS' during ischemic and pharmacological preconditioning [15].”
From Differential effects of complex II on mitochondrial ROS production and their relation to cardioprotective pre- and postconditioning (2013) · cites this paper as [15]
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- Authors
- Dröse, S., Hanley, P. J., & Brandt, U.
- Affiliations
- Goethe University Frankfurt (DE)
- University of Münster (DE)
- Corresponding author
- Brandt, Ulrich
- Venue
- Biochimica et Biophysica Acta (BBA) - General Subjects
- Publisher
- Elsevier BV
- Published
- 2009-06
- Volume
- 1790
- Issue
- 6
- Pages
- 558-565
- ISSN
- 0304-4165 (ISSN-L)
- OpenAlex
- W2068063220
- Cited by
- 72
- References
- 48
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 1 · 2023: 2 · 2022: 2 · 2021: 3 · 2020: 5 · 2019: 5 · 2018: 4 · 2017: 2 · 2016: 5 · 2015: 5 · 2014: 9 · 2013: 6 · 2012: 6
- FWCI
- 2.68
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biochimica et Biophysica Acta (BBA) - General Subjects (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Deutsche Forschungsgemeinschaft
- Goethe-Universität Frankfurt am Main
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Pathology and Forensic Medicine › Cardiac Ischemia and Reperfusion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- diazoxide, mitochondrial reactive oxygen species, respiratory chain complex I, respiratory chain complex III, complex II inhibition, reverse electron transfer, mitochondrial uncoupling, 5-hydroxydecanoate, mitochondrial KATP channels, ischemia-reperfusion injury, preconditioning, hydrogen peroxide production, submitochondrial particles, rat heart mitochondria
- MeSH terms
- Animals, Cattle, Diazoxide, Hydrogen Peroxide, Mitochondria, Heart, Submitochondrial Particles, Electron Transport Complex III, Vasodilator Agents, Oxidants, Reactive Oxygen Species, Electron Transport Complex II, Electron Transport Complex I, Rats
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