Soluble adenylyl cyclase regulates the cytosolic NADH/NAD+ redox state and the bioenergetic switch between glycolysis and oxidative phosphorylation
Autor: | Lonny R. Levin, Arthur J. Verhoeven, Eduardo H. Gilglioni, Hang Lam Li, Richard J. Rodenburg, Simei Go, Daan M. Panneman, Jung-Chin Chang, Ronald P.J. Oude Elferink, Suzanne Duijst, Jochen Buck, Hsu-Li Huang |
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Přispěvatelé: | Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology Endocrinology Metabolism, Graduate School |
Jazyk: | angličtina |
Rok vydání: | 2021 |
Předmět: |
0301 basic medicine
Biophysics NADH/NAD redox state Adenylate kinase Oxidative phosphorylation Biochemistry 03 medical and health sciences 0302 clinical medicine Protein kinase A Glycolysis education education.field_of_study Exchange protein directly activated by cAMP (Epac) Chemistry Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6] Cell Biology Soluble adenylyl cyclase Cell biology 030104 developmental biology Mitochondrial respiratory chain Anaerobic glycolysis NAD+ kinase 030217 neurology & neurosurgery |
Zdroj: | BIOCHIMICA ET BIOPHYSICA ACTA-BIOENERGETICS, 1862(4):148367. Elsevier Biochimica et Biophysica Acta. Bioenergetics, 1862, 4 Biochimica et Biophysica Acta. Bioenergetics, 1862 |
ISSN: | 0005-2728 |
Popis: | Contains fulltext : 231545.pdf (Publisher’s version ) (Open Access) The evolutionarily conserved soluble adenylyl cyclase (sAC, ADCY10) mediates cAMP signaling exclusively in intracellular compartments. Because sAC activity is sensitive to local concentrations of ATP, bicarbonate, and free Ca(2+), sAC is potentially an important metabolic sensor. Nonetheless, little is known about how sAC regulates energy metabolism in intact cells. In this study, we demonstrated that both pharmacological and genetic suppression of sAC resulted in increased lactate secretion and decreased pyruvate secretion in multiple cell lines and primary cultures of mouse hepatocytes and cholangiocytes. The increased extracellular lactate-to-pyruvate ratio upon sAC suppression reflected an increased cytosolic free [NADH]/[NAD(+)] ratio, which was corroborated by using the NADH/NAD(+) redox biosensor Peredox-mCherry. Mechanistic studies in permeabilized HepG2 cells showed that sAC inhibition specifically suppressed complex I of the mitochondrial respiratory chain. A survey of cAMP effectors revealed that only selective inhibition of exchange protein activated by cAMP 1 (Epac1), but not protein kinase A (PKA) or Epac2, suppressed complex I-dependent respiration and significantly increased the cytosolic NADH/NAD(+) redox state. Analysis of the ATP production rate and the adenylate energy charge showed that inhibiting sAC reciprocally affects ATP production by glycolysis and oxidative phosphorylation while maintaining cellular energy homeostasis. In conclusion, our study shows that, via the regulation of complex I-dependent mitochondrial respiration, sAC-Epac1 signaling regulates the cytosolic NADH/NAD(+) redox state, and coordinates oxidative phosphorylation and glycolysis to maintain cellular energy homeostasis. As such, sAC is effectively a bioenergetic switch between aerobic glycolysis and oxidative phosphorylation at the post-translational level. |
Databáze: | OpenAIRE |
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