Soluble adenylyl cyclase regulates the cytosolic NADH/NAD+ redox state and the bioenergetic switch between glycolysis and oxidative phosphorylation

Chang, Jung-Chin; Go, Simei; Gilglioni, Eduardo Hideo; Duijst, Suzanne; Panneman, Daan M.; Rodenburg, Richard J.; Li, Hang Lam; Huang, Hsu-Li; Levin, Lonny R.; Buck, Jochen; Verhoeven, Arthur J.; Elferink, Ronald P.J. Oude

doi:10.1016/j.bbabio.2020.148367

Cited by 13 publications

(16 citation statements)

References 90 publications

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“…These cAMP effects were mediated via PGC-1αdependant induction of mitochondrial biogenesis and improved mitochondrial function. In line with this, Chang and colleagues [100] recently showed that transient pharmacological suppression of sAC activity in various primary and cancer cell lines results in inhibition of OXPHOS and a metabolic shift towards glycolysis. This metabolic shift seems to be due to reduced activity of complex I resulting from the mitochondrial sAC inactivation.…”

Section: Cancermentioning

confidence: 69%

Regulation of Mitochondrial Homeostasis by sAC-Derived cAMP Pool: Basic and Translational Aspects

Aslam

Ladilov

2021

Cells

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In contrast to the traditional view of mitochondria being solely a source of cellular energy, e.g., the “powerhouse” of the cell, mitochondria are now known to be key regulators of numerous cellular processes. Accordingly, disturbance of mitochondrial homeostasis is a basic mechanism in several pathologies. Emerging data demonstrate that 3′–5′-yclic adenosine monophosphate (cAMP) signalling plays a key role in mitochondrial biology and homeostasis. Mitochondria are equipped with an endogenous cAMP synthesis system involving soluble adenylyl cyclase (sAC), which localizes in the mitochondrial matrix and regulates mitochondrial function. Furthermore, sAC localized at the outer mitochondrial membrane contributes significantly to mitochondrial biology. Disturbance of the sAC-dependent cAMP pools within mitochondria leads to mitochondrial dysfunction and pathology. In this review, we discuss the available data concerning the role of sAC in regulating mitochondrial biology in relation to diseases.

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Section: Cancermentioning

confidence: 69%

Regulation of Mitochondrial Homeostasis by sAC-Derived cAMP Pool: Basic and Translational Aspects

Aslam

Ladilov

2021

Cells

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“…The conversion of glycogen phosphorylase from the inactive T state to the active R state is stimulated allosterically by AMP and covalently by phosphorylase kinase-mediated phosphorylation at residue Ser-15 (Johnson, 1992). Since sAC inhibition did not cause changes in total ATP production, the adenylate energy charge, or the level of AMP (data not shown) both in the absence (Figure S1E and S1F) and presence (Chang et al, 2021) of glucose, we hypothesized that sAC regulates the phosphorylation state of glycogen phosphorylase. To avoid inadvertent activation of AMPK during glucose deprivation, we performed these experiments in the presence of a physiological concentration of glucose (5.5 mM).…”

Section: Resultsmentioning

confidence: 91%

“…We and others have shown that sAC regulates the activity of complex I of the respiratory chain (Chang et al, 2021; De Rasmo et al, 2015; Valsecchi et al, 2017). Inhibition of complex I can reduce the steady state glycogen level via AMPK-dependent suppression of glycogen synthase activity (Bultot et al, 2012; Carling and Hardie, 1989; Heinz et al, 2017).…”

Section: Resultsmentioning

confidence: 97%

“…Calculation of the concomitant ATP production rates showed that ATP production by glycolysis was transiently stimulated upon sAC inhibition, while ATP production by TCA cycle and oxidative phosphorylation were transiently suppressed (Figure S1A-S1D). During these transient changes in ECAR and OCAR, the overall ATP production (Figure S1E) and the adenylate energy charge (Figure S1F) remained constant, indicating that sAC co-ordinates ATP production of glycolysis and oxidative phosphorylation to maintain energy homeostasis not only during glucose-sufficient conditions (Chang et al, 2021), but also during glucose deprivation. Since glycogen is the primary glucose reserve in cells during glycose deprivation, we tested the hypothesis that in the absence of glucose sAC inhibition mobilized glycogen to cause a transient increase in glycolytic flux.…”

Section: Resultsmentioning

confidence: 99%

“…Importantly, sAC is expressed in almost all tissues examined (Geng et al, 2005; Levin and Buck, 2015). We have recently shown that sAC acts as an acute switch for aerobic glycolysis and oxidative phosphorylation maintaining the autonomous energy metabolism of cells (Chang et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

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Opposite regulation of glycogen metabolism by cAMP produced in the cytosol and at the plasma membrane

Verhoeven

Bizerra

Gilglioni

et al. 2022

Preprint

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Cyclic AMP is produced in cells by two different types of adenylyl cyclases: at the plasma membrane by the transmembrane adenylyl cyclases (tmACs, ADCY1~ADCY9) and in the cytosol by the evolutionarily more conserved soluble adenylyl cyclase (sAC, ADCY10). By employing high-resolution extracellular flux analysis to study glycogen breakdown in real time, we show here thatcAMP regulates glycogen metabolism in opposite directions depending on its location of synthesis within cells. While the canonical tmAC-cAMP-PKA axis promotes glycogenolysis, we demonstrate that the non-canonical sAC-cAMP-Epac1 signalling suppresses glycogenolysis in a variety of cell types. Our findings demonstrate the importance of cAMP microdomain organization in glycogen metabolism and reveal a novel role of sAC in energy metabolism during glucose deprivation.

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Gray and white matter astrocytes differ in basal metabolism but respond similarly to neuronal activity

Köhler

Winkler

Junge

et al. 2022

Glia

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Astrocytes are a heterogeneous population of glial cells in the brain, which adapt their properties to the requirements of the local environment. Two major groups of astrocytes are protoplasmic astrocytes residing in gray matter as well as fibrous astrocytes of white matter. Here, we compared the energy metabolism of astrocytes in the cortex and corpus callosum as representative gray matter and white matter regions, in acute brain slices taking advantage of genetically encoded fluorescent nanosensors for the NADH/NAD + redox ratio and for ATP.Astrocytes of the corpus callosum presented a more reduced basal NADH/NAD + redox ratio, and a lower cytosolic concentration of ATP compared to cortical astrocytes. In cortical astrocytes, the neurotransmitter glutamate and increased extracellular concentrations of K + , typical correlates of neuronal activity, induced a more reduced NADH/NAD + redox ratio. While application of glutamate decreased [ATP], K + as well as the combination of glutamate and K + resulted in an increase of ATP levels. Strikingly, a very similar regulation of metabolism by K + and glutamate was observed in astrocytes in the corpus callosum. Finally, strong intrinsic neuronal activity provoked by application of bicuculline and withdrawal of Mg 2+ caused a shift of the NADH/NAD + redox ratio to a more reduced state as well as a slight reduction of [ATP] in gray and white matter astrocytes. In summary, the metabolism of astrocytes in cortex and corpus callosum shows distinct basal properties, but qualitatively similar responses to neuronal activity, probably reflecting the different environment and requirements of these brain regions.

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Soluble adenylyl cyclase regulates the cytosolic NADH/NAD+ redox state and the bioenergetic switch between glycolysis and oxidative phosphorylation

Cited by 13 publications

References 90 publications

Regulation of Mitochondrial Homeostasis by sAC-Derived cAMP Pool: Basic and Translational Aspects

Regulation of Mitochondrial Homeostasis by sAC-Derived cAMP Pool: Basic and Translational Aspects

Opposite regulation of glycogen metabolism by cAMP produced in the cytosol and at the plasma membrane

Gray and white matter astrocytes differ in basal metabolism but respond similarly to neuronal activity

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