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Regulation of AMPK activity by type 10 adenylyl cyclase: contribution to the mitochondrial biology, cellular redox and energy homeostasis

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Abstract

The downregulation of AMP-activated protein kinase (AMPK) activity contributes to numerous pathologies. Recent reports suggest that the elevation of cellular cAMP promotes AMPK activity. However, the source of the cAMP pool that controls AMPK activity remains unknown. Mammalian cells possess two cAMP sources: membrane-bound adenylyl cyclase (tmAC) and intracellularly localized, type 10 soluble adenylyl cyclase (sAC). Due to the localization of sAC and AMPK in similar intracellular compartments, we hypothesized that sAC may control AMPK activity. In this study, sAC expression and activity were manipulated in H9C2 cells, adult rat cardiomyocytes or endothelial cells. sAC knockdown depleted the cellular cAMP content and decreased AMPK activity in an EPAC-dependent manner. Functionally, sAC knockdown reduced cellular ATP content, increased mitochondrial ROS formation and led to mitochondrial depolarization. Furthermore, sAC downregulation led to EPAC-dependent mitophagy disturbance, indicated by an increased mitochondrial mass and unaffected mitochondrial biogenesis. Consistently, sAC overexpression or stimulation with bicarbonate significantly increased AMPK activity and cellular ATP content. In contrast, tmAC inhibition or stimulation produced no effect on AMPK activity. Therefore, the sAC–EPAC axis may regulate basal and induced AMPK activity and support mitophagy, cellular energy and redox homeostasis. The study argues for sAC as a potential target in treating pathologies associated with AMPK downregulation.

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Abbreviations

ACC:

Acetyl-CoA carboxylase

AMP:

Adenosine monophosphate

ADP:

Adenosine diphosphate

AMPK:

AMP-activated protein kinase

ATP:

Adenosine triphosphate

cAMP:

3′-5′-Cyclic adenosine monophosphate

CFP:

Cyan fluorescence protein

Drp1:

Dynamin-like protein 1

EPAC:

Exchange protein activated by cAMP

FRET:

Föster resonance energy transfer

GFP:

Green fluorescence protein

LKB1:

Liver kinase B1

MFF:

Mitochondrial fission factor

PDE:

Phosphodiesterase

PGC1α:

Peroxisome proliferator-activated receptor‑γ co-activator 1α

PKA:

Protein kinase A

ROS:

Reactive oxygen species

sAC:

Soluble adenylyl cyclase

TFAM:

Mitochondrial transcription factor A

tmAC:

Transmembrane adenylyl cyclase

ULK1:

unc-51 like autophagy activating kinase 1

YFP:

Yellow fluorescence protein

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Acknowledgements

We would like to express our gratitude to N. Haritonow, A. Kuehne, V. Riese, S. Pozdniakova and E. Dworatzek for their assistance with the theoretical and technical components of this research. This study was supported by the European Union (Radox Grant FP7-PEOPLE-2012-ITN) to VRZ, by DZHK (German Centre for Cardiovascular Research) partner site Berlin (Grant 81Z2100201) to VRZ and by Margarete-Ammon foundation to VRZ. Parts of the study were part of V. Jayarajan’s thesis project submitted in fulfillment of the requirements for the degree of Doctor of Philosophy at the Freie Universität Berlin (Germany).

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Authors and Affiliations

  1. Charité, Universitätsmedizin Berlin, Institute of Gender in Medicine, Center for Cardiovascular Research, Berlin, Germany

    Vignesh Jayarajan, Vera Regitz-Zagrosek & Yury Ladilov

  2. DZHK (German Center for Cardiovascular Research), Berlin Partner Site, Berlin, Germany

    Vignesh Jayarajan, Vera Regitz-Zagrosek & Yury Ladilov

  3. Department of Clinical Pharmacology, Ruhr-University Bochum, Bochum, Germany

    Vignesh Jayarajan, Avinash Appukuttan & Peter Reusch

  4. Internal Medicine I/Cardiology and Angiology, University Hospital of Giessen and Marburg, Giessen, Germany

    Muhammad Aslam

  5. Experimental Cardiology, Justus Liebig University Giessen, Giessen, Germany

    Muhammad Aslam

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  1. Vignesh Jayarajan
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  2. Avinash Appukuttan
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Jayarajan, V., Appukuttan, A., Aslam, M. et al. Regulation of AMPK activity by type 10 adenylyl cyclase: contribution to the mitochondrial biology, cellular redox and energy homeostasis. Cell. Mol. Life Sci. 76, 4945–4959 (2019). https://doi.org/10.1007/s00018-019-03152-y

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