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Cellular and Molecular Life Sciences

, Volume 76, Issue 24, pp 4945–4959 | Cite as

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

  • Vignesh Jayarajan
  • Avinash Appukuttan
  • Muhammad Aslam
  • Peter Reusch
  • Vera Regitz-Zagrosek
  • Yury LadilovEmail author
Original Article
  • 321 Downloads

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.

Keywords

ADCY10 cAMP AMPK ROS ATP Mitophagy 

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

Notes

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).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

18_2019_3152_MOESM1_ESM.pdf (495 kb)
Supplementary material 1 (PDF 496 kb)

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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Charité, Universitätsmedizin Berlin, Institute of Gender in Medicine, Center for Cardiovascular ResearchBerlinGermany
  2. 2.DZHK (German Center for Cardiovascular Research)BerlinGermany
  3. 3.Department of Clinical PharmacologyRuhr-University BochumBochumGermany
  4. 4.Internal Medicine I/Cardiology and AngiologyUniversity Hospital of Giessen and MarburgGiessenGermany
  5. 5.Experimental CardiologyJustus Liebig University GiessenGiessenGermany

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