Journal article
Hepatic glutamic-oxaloacetic transaminase (GOT2) promotes mitochondrial respiration energized at complex II and alters whole body metabolism
The Journal of biological chemistry, Vol.301(6), 110261
06/2025
DOI: 10.1016/j.jbc.2025.110261
PMCID: PMC12212131
PMID: 40409551
Abstract
The mitochondrial enzyme, glutamic-oxaloacetic transaminase (GOT2), catalyzes the reaction between oxaloacetate and glutamate generating aspartate and alpha-ketoglutarate (α-KG). Glutamate can also be directly converted to α-KG by glutamate dehydrogenase. We investigated mitochondrial and systemic effects of an inducible liver specific-mouse GOT2 knockout (KO). We observed no differences in body mass or percent fat mass in KO mice, however, KO mice had lower fasting glucose and liver tissue contained more fat. Respiration by liver mitochondria energized at complex II by succinate + glutamate was decreased in KO compared to wildtype (WT) mice at low inner membrane potential (ΔΨ) as induced by titration with ADP. Metabolite studies by NMR showed that at low versus high ΔΨ, GOT2KO mitochondria energized by succinate + glutamate generated more oxaloacetate (a potent inhibitor of succinate dehydrogenase, SDH) and less aspartate. Respiration and mitochondrial metabolites energized by pyruvate + malate or palmitoyl-carnitine + malate did not differ between KO and WT mice. Respiration by GOT2KO mitochondria energized by glutamate + malate was decreased at all levels of ΔΨ. Pathway analysis of LC-MS profile data in liver tissue of KO versus WT mice revealed differential enrichment of the malate aspartate shuttle, TCA cycle, aspartate metabolism, glutamate metabolism, and gluconeogenesis. In summary, GOT2KO impaired potential-dependent complex II energized O
flux likely due at least in part to oxaloacetate inhibition of SDH.
Details
- Title: Subtitle
- Hepatic glutamic-oxaloacetic transaminase (GOT2) promotes mitochondrial respiration energized at complex II and alters whole body metabolism
- Creators
- Brian D Fink - University of IowaRitu Som - University of IowaAdam J Rauckhorst - University of IowaEric B Taylor - University of IowaLiping Yu - University of IowaWilliam I Sivitz - University of Iowa
- Resource Type
- Journal article
- Publication Details
- The Journal of biological chemistry, Vol.301(6), 110261
- DOI
- 10.1016/j.jbc.2025.110261
- PMID
- 40409551
- PMCID
- PMC12212131
- NLM abbreviation
- J Biol Chem
- ISSN
- 1083-351X
- eISSN
- 1083-351X
- Publisher
- ELSEVIER
- Grant note
- NIH: R01 DK123043, R01 DK104998, R01 DK138664 American Heart Association: CDA851976 U.S. Department of Veterans Affairs, Biomedical Laboratory Research and Development Service: 2 I01 BX000285-06
These studies were supported by the NIH awards, R01 DK123043 (W. I. S.) , R01 DK104998 (E. B. T.) . and R01 DK138664 (E. B. T.) . The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Also supported by CDA851976 (A. J. R.) from the American Heart Association, Merit Review Award 2 I01 BX000285-06 (W. I. S.) from the U.S. Department of Veterans Affairs, Biomedical Laboratory Research and Development Service, resources, and the use of facilities at the Department of Veterans Affairs Health Care System, Iowa City, IA 52246, and by the Iowa Fraternal Order of the Eagles (W. I. S.) .
- Language
- English
- Electronic publication date
- 05/21/2025
- Date published
- 06/2025
- Academic Unit
- Molecular Physiology and Biophysics; Pathology; Fraternal Order of Eagles Diabetes Research Center; Neuroscience and Pharmacology; Biochemistry and Molecular Biology; Medicine Administration; Endocrinology and Metabolism; Internal Medicine
- Record Identifier
- 9984824330102771
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