ArticleThe Journal of biological chemistry2014
A role for mitochondrial phosphoenolpyruvate carboxykinase (PEPCK-M) in the regulation of hepatic gluconeogenesis.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 49 papers.
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Who cites it
49 citing papers in PubMed, 105 citations in OpenAlex.
- SLC25A35 carrier endows mitochondrial phosphoenolpyruvate with glyceroneogenesis.Life metabolism · 2026Article
- Review
- Mitochondrial control of glycerolipid synthesis by a PEP shuttle.bioRxiv : the preprint server for biology · 2026Article
- Effects of Temperature and Salinity on Ovarian Development and Differences in Energy Metabolism Between Reproduction and Growth During Ovarian Development in theInternational journal of molecular sciences · 2025Article
- Dietary supplementation of grape seed proanthocyanidins improves growth performance, carcass traits, and meat quality in growing-finishing pigs.Animal nutrition (Zhongguo xu mu shou yi xue hui) · 2025Article
- Fish MicroRNA Responses to Thermal Stress: Insights and Implications for Aquaculture and Conservation Amid Global Warming.Animals : an open access journal from MDPI · 2025Review
- The Synergistic Impact of Glycolysis, Mitochondrial OxPhos, and PEP Cycling on ATP Production in Beta Cells.International journal of molecular sciences · 2025Article
- The Glucose-Succinate Pathway: A Crucial Anaerobic Metabolic Pathway in the ScallopInternational journal of molecular sciences · 2024Article
- Gluconeogenesis in the extraembryonic yolk syncytial layer of the zebrafish embryo.PNAS nexus · 2024Article
- Phosphoenolpyruvate carboxykinase 2-mediated metabolism promotes lung tumorigenesis by inhibiting mitochondrial-associated apoptotic cell death.Frontiers in pharmacology · 2024Article
- The Roles of NFR2-Regulated Oxidative Stress and Mitochondrial Quality Control in Chronic Liver Diseases.Antioxidants (Basel, Switzerland) · 2023Review
- Emerging roles of cytosolic phosphoenolpyruvate kinase 1 (PCK1) in cancer.Biochemistry and biophysics reports · 2023Review
- The Beneficial Effect of Mitochondrial Transfer Therapy in 5XFAD Mice via Liver-Serum-Brain Response.Cells · 2023Article
- The SLC25A47 locus controls gluconeogenesis and energy expenditure.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Liver Regeneration and Immunity: A Tale to Tell.International journal of molecular sciences · 2023Review
- Ketosis Alters Transcriptional Adaptations of Subcutaneous White Adipose Tissue in Holstein Cows during the Transition Period.Animals : an open access journal from MDPI · 2022Article
- Metabolic cycles and signals for insulin secretion.Cell metabolism · 2022Review
- Exploring synthetic biology for the development of a sensor cell line for automated bioprocess control.Scientific reports · 2022Article
- [Communications biology · 2022Article
- Simulation of the crosstalk between glucose and acetaminophen metabolism in a liver zonation model.Frontiers in pharmacology · 2022Article
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Authors and funding
13 authors at 4 institutions in 2 countries.
Funding
Abstract
Synthesis of phosphoenolpyruvate (PEP) from oxaloacetate is an absolute requirement for gluconeogenesis from mitochondrial substrates. Generally, this reaction has solely been attributed to the cytosolic isoform of PEPCK (PEPCK-C), although loss of the mitochondrial isoform (PEPCK-M) has never been assessed. Despite catalyzing the same reaction, to date the only significant role reported in mammals for the mitochondrial isoform is as a glucose sensor necessary for insulin secretion. We hypothesized that this nutrient-sensing mitochondrial GTP-dependent pathway contributes importantly to gluconeogenesis. PEPCK-M was acutely silenced in gluconeogenic tissues of rats using antisense oligonucleotides both in vivo and in isolated hepatocytes. Silencing PEPCK-M lowers plasma glucose, insulin, and triglycerides, reduces white adipose, and depletes hepatic glycogen, but raises lactate. There is a switch of gluconeogenic substrate preference to glycerol that quantitatively accounts for a third of glucose production. In contrast to the severe mitochondrial deficiency characteristic of PEPCK-C knock-out livers, hepatocytes from PEPCK-M-deficient livers maintained normal oxidative function. Consistent with its predicted role, gluconeogenesis rates from hepatocytes lacking PEPCK-M are severely reduced for lactate, alanine, and glutamine, but not for pyruvate and glycerol. Thus, PEPCK-M has a direct role in fasted and fed glucose homeostasis, and this mitochondrial GTP-dependent pathway should be reconsidered for its involvement in both normal and diabetic metabolism.
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