Proton‐translocating transhydrogenase and NAD‐ and NADP‐linked isocitrate dehydrogenases operate in a substrate cycle which contributes to fine regulation of the tricarboxylic acid cycle activity in mitochondria
Abstract
H+‐transhydrogenase (H+‐Thase) and NADP‐linked isocitrate dehydrogenase (NADP—ICDH) are very active in animal mitochondria but their physiological function is only poorly understood. This is especially so in the case of the heart and muscle, where there are no major consumers of NADPH. We propose here that H+‐Thase and NADP—ICDH have a combined function in the fine regulation of the activity of the tricarboxylic acid (TCA) cycle, providing enhanced sensitivy to changes in energy demand. This is achieved through cycling of substrates by NAD‐linked ICDH, NADP‐linked ICDH and H+‐Thase. It is proposed that NAD—ICDH operates in the forward direction of the TCA cycle, but NADP—ICDH is driven in reverse by elevated levels of NADPH resulting from the action of the transmembrane proton electrochemical potential gradient (Δp) on H+‐Thase. This has the effect of increasing the sensitivity to allosteric modifiers of NAD—ICDH (NADH, ADP, ATP, Ca 2+ etc), potentially giving rise to large changes in the net flux from iso‐citrate to α‐ketoglutarate. Furthermore, changes in the level of Δp resulting from changes in the demand for ATP would, via H+‐Thase, shift the redox state of the NADP pool and this, in turn, would lead to a change in the rate of the reaction catalysed by NADP—ICDH and hence to an additional and complementary effect on the net metabolic flux from isocitrate to α‐ketoglutarate. Other consequences of this substrate cycle are, (i) the production of heat at the expense of Δp, which may contribute to thermoregulation in the animal, and (ii) an increased rate of dissipation of Δp (leak).
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Alternatively, substrate flow through the TCA cycle differs depending on substrates, which might affect the activity of NADP+-dependent isocitrate dehydrogenase and malic enzyme.
“Alternatively, the substrate flow through the TCA cycle differs depending on the substrates, which might affect the activity of the other two mitochondrial NADPH-regenerating enzymes the NADP + -dependent isocitrate dehydrogenase [119,120] and the malic enzyme [118,121].”
From Differential effects of complex II on mitochondrial ROS production and their relation to cardioprotective pre- and postconditioning (2013) · cites this paper as [119]
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- Authors
- Sazanov, L. A., & Jackson, J. B.
- Affiliations
- University of Birmingham (GB)
- Corresponding author
- Jackson, J.B.
- ORCID
- Sazanov, L.A.
- Venue
- FEBS Letters
- Publisher
- Wiley
- Published
- 1994-05-16
- Volume
- 344
- Issue
- 2-3
- Pages
- 109-116
- ISSN
- 0014-5793 (ISSN-L)
- 1873-3468
- OpenAlex
- W2072885613
- Cited by
- 205
- References
- 49
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 4 · 2023: 4 · 2022: 2 · 2021: 6 · 2020: 4 · 2019: 7 · 2018: 8 · 2017: 2 · 2016: 6 · 2015: 7 · 2014: 9 · 2013: 12 · 2012: 12
- FWCI
- 0.96
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- FEBS Letters (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Wellcome Trust
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Biochemical Acid Research Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › ATP Synthase and ATPases Research
- Keywords
- mitochondrial metabolism, NADPH, alpha-ketoglutarate, allosteric regulation, metabolic flux, thermoregulation, proton leak
- MeSH terms
- Animals, Citric Acid Cycle, Isocitrate Dehydrogenase, Mitochondria, Models, Biological, NAD, NADP, NADP Transhydrogenases, Substrate Specificity
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