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Adropin regulates pyruvate dehydrogenase in cardiac cells via a novel GPCR-MAPK-PDK4 signaling pathway
- Source :
- Redox Biology, Vol 18, Iss, Pp 25-32 (2018), Redox Biology
- Publication Year :
- 2018
- Publisher :
- Elsevier, 2018.
-
Abstract
- Mitochondria supply ~90% of the ATP required for contractile function in cardiac cells. While adult cardiomyocytes preferentially utilize fatty acids as a fuel source for oxidative phosphorylation, cardiac mitochondria can switch to other substrates when required. This change is driven in part by a combination of extracellular and intracellular signal transduction pathways that alter mitochondrial gene expression and enzymatic activity. The mechanisms by which extracellular metabolic information is conveyed to cardiac mitochondria are not currently well defined. Recent work has shown that adropin – a liver-secreted peptide hormone – can induce changes in mitochondrial fuel substrate utilization in skeletal muscle, leading to increased glucose use. In this study, we examined whether adropin could regulate mitochondrial glucose utilization pathways in cardiac cells. We show that stimulation of cultured cardiac cells with adropin leads to decreased expression of the pyruvate dehydrogenase (PDH) negative regulator PDK4, which reduces inhibitory PDH phosphorylation. The downregulation of PDK4 expression by adropin is lost when GPR19 – a putative adropin receptor – is genetically depleted in H9c2 cells. Loss of GRP19 expression alone increased PDK4 expression, leading to a reduction in mitochondrial respiration. Finally, we show that adropin-mediated GPR19 signaling relies on the p44/42 MAPK pathway, and that pharmacological disruption of this pathway blocks the effects of adropin on PDK4 in cardiac cells. These findings suggest that adropin may be a key regulator of fuel substrate utilization in the heart, and implicates an orphan G-protein coupled receptor in a novel signaling pathway controlling mitochondrial fuel metabolism.<br />Graphical abstract fx1
- Subjects :
- 0301 basic medicine
MAPK/ERK pathway
Clinical Biochemistry
PDK4
Nerve Tissue Proteins
Pyruvate Dehydrogenase Complex
Adropin
Oxidative phosphorylation
Protein Serine-Threonine Kinases
Mitochondrion
Biochemistry
Mitochondria, Heart
Cell Line
Receptors, G-Protein-Coupled
03 medical and health sciences
GPCR
Animals
Myocytes, Cardiac
Phosphorylation
lcsh:QH301-705.5
Mitogen-Activated Protein Kinase Kinases
lcsh:R5-920
Chemistry
Organic Chemistry
Pyruvate Dehydrogenase Acetyl-Transferring Kinase
Blood Proteins
Pyruvate dehydrogenase complex
Mitochondria
Rats
Receptors, Neurotransmitter
3. Good health
Cell biology
Intracellular signal transduction
Metabolism
030104 developmental biology
lcsh:Biology (General)
GRP19
Pyruvate dehydrogenase
Signal transduction
Peptides
lcsh:Medicine (General)
Research Paper
Signal Transduction
Subjects
Details
- Language :
- English
- ISSN :
- 22132317
- Volume :
- 18
- Database :
- OpenAIRE
- Journal :
- Redox Biology
- Accession number :
- edsair.doi.dedup.....8cc33bc565bf82a0782be1772ad5e3f0