Journal article
Oxaloacetic acid mediates ADP-dependent inhibition of mitochondrial complex II-driven respiration
The Journal of biological chemistry, Vol.293(51), pp.19932-19941
12/21/2018
DOI: 10.1074/jbc.RA118.005144
PMCID: PMC6314144
PMID: 30385511
Abstract
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 H2O2 (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.
Details
- Title: Subtitle
- Oxaloacetic acid mediates ADP-dependent inhibition of mitochondrial complex II-driven respiration
- Creators
- Brian D. Fink - University of IowaFan Bai - University of IowaLiping Yu - University of IowaRyan D. Sheldon - University of IowaArpit Sharma - University of IowaEric B. Taylor - University of IowaWilliam I. Sivitz - University of Iowa
- Resource Type
- Journal article
- Publication Details
- The Journal of biological chemistry, Vol.293(51), pp.19932-19941
- DOI
- 10.1074/jbc.RA118.005144
- PMID
- 30385511
- PMCID
- PMC6314144
- NLM abbreviation
- J Biol Chem
- ISSN
- 0021-9258
- eISSN
- 1083-351X
- Publisher
- Amer Soc Biochemistry Molecular Biology Inc
- Number of pages
- 10
- Grant note
- R01DK104998 / NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) T32HL007344 / NATIONAL HEART, LUNG, AND BLOOD INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI) P30CA086862 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) Fraternal Order of the Eagles R01 DK104998; F32 DK116522 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA
- Language
- English
- Date published
- 12/21/2018
- Academic Unit
- Molecular Physiology and Biophysics; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Medicine Administration; Endocrinology and Metabolism; Internal Medicine
- Record Identifier
- 9984297511502771
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