Oxaloacetic acid mediates ADP-dependent inhibition of mitochondrial complex II-driven respiration
Open accessAbstract
We recently reported a previously unrecognized mitochondrial respiratory phenomenon. When [ADP] was held constant ("clamped") at sequentially increasing concentrations in succinate-energized muscle mitochondria in the absence of rotenone (commonly used to block complex I), we observed a biphasic, increasing then decreasing, respiratory response. Here we investigated the mechanism. We confirmed decades-old reports that oxaloacetate (OAA) inhibits succinate dehydrogenase (SDH). We then used an NMR method to assess OAA concentrations (known as difficult to measure by MS) as well as those of malate, fumarate, and citrate in isolated succinate-respiring mitochondria. When these mitochondria were incubated at varying clamped ADP concentrations, respiration increased at low [ADP] as expected given the concurrent reduction in membrane potential. With further increments in [ADP], respiration decreased associated with accumulation of OAA. Moreover, a low pyruvate concentration, that alone was not enough to drive respiration, was sufficient to metabolize OAA to citrate and completely reverse the loss of succinate-supported respiration at high [ADP]. Further, chemical or genetic inhibition of pyruvate uptake prevented OAA clearance and preserved respiration. In addition, we measured the effects of incremental [ADP] on NADH, superoxide, and H 2 O 2 (a marker of reverse electron transport from complex II to I). In summary, our findings, taken together, support a mechanism (detailed within) wherein succinate-energized respiration as a function of increasing [ADP] is initially increased by [ADP]-dependent effects on membrane potential but subsequently decreased at higher [ADP] by inhibition of succinate dehydrogenase by OAA. The physiologic relevance is discussed.
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SDH undergoes allosteric inhibition by OAA, slowing the cycle upon insufficient acetyl-CoA availability.
“Apart from the three regulatory enzymes, SDH undergoes allosteric inhibition by OAA, slowing the cycle down upon insufficient acetyl-CoA availability (137).”
From Regulation and function of the mammalian tricarboxylic acid cycle (2023) · cites this paper as [137]
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Regulation and function of the mammalian tricarboxylic acid cycle
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“Apart from the three regulatory enzymes, SDH undergoes allosteric inhibition by OAA, slowing the cycle down upon insufficient acetyl-CoA availability (137).”
Background
- Authors
- Fink, B. D., Bai, F., Yu, L., Sheldon, R. D., Sharma, A., Taylor, E. B., & Sivitz, W. I.
- Affiliations
- University of Iowa (US)
- Corresponding author
- Sivitz, William I.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2018-12
- Volume
- 293
- Issue
- 51
- Pages
- 19932-19941
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC6314144
- OpenAlex
- W2898849930
- Cited by
- 54
- References
- 37
- Citations by year
- 2026: 5 · 2025: 11 · 2024: 10 · 2023: 7 · 2022: 4 · 2021: 8 · 2020: 3 · 2019: 6
- FWCI
- 1.51
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Center for Integrated Healthcare, U.S. Department of Veterans Affairs (CIH, VA) (5101BX000285–06)
- Iowa Fraternal Order of the Eagles
- HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (R01 DK104998, F32 DK116522)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › ATP Synthase and ATPases Research
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- oxaloacetate, succinate dehydrogenase inhibition, succinate dehydrogenase, pyruvate metabolism, citrate, membrane potential, reverse electron transfer, superoxide, hydrogen peroxide, muscle mitochondria
- MeSH terms
- Adenosine Diphosphate, Animals, Energy Metabolism, Enzyme Inhibitors, Mitochondria, Oxygen, Rats, Sprague-Dawley, Reactive Oxygen Species, Cell Respiration, Muscle Cells, Electron Transport Complex II, Rats, Oxaloacetic Acid
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