Compromised energetics in the adenylate kinase AK1 gene knockout heart under metabolic stress

Darko Pucar, Edwin Janssen, Petras P. Dzeja, Nenad Juranic, Slobodan Macura, Bé Wieringa, Andre Terzic

Research output: Contribution to journalArticle

69 Scopus citations

Abstract

Rapid exchange of high energy carrying molecules between intracellular compartments is essential in sustaining cellular energetic homeostasis. Adenylate kinase (AK)-catalyzed transfer of adenine nucleotide β- and γ-phosphoryls has been implicated in intracellular energy communication and nucleotide metabolism. To demonstrate the significance of this reaction in cardiac energetics, phosphotransfer dynamics were determined by [18O]phosphoryl oxygen analysis using 31P NMR and mass spectrometry. In hearts with a null mutation of the AK1 gene, which encodes the major AK isoform, total AK activity and β-phosphoryl transfer was reduced by 94% and 36%, respectively. This was associated with up-regulation of phosphoryl flux through remaining minor AK isoforms and the glycolytic phosphotransfer enzyme, 3-phosphoglycerate kinase. In the absence of metabolic stress, deletion of AK1 did not translate into gross abnormalities in nucleotide levels, γ-ATP turnover rate or creatine kinase-catalyzed phosphotransfer. However, under hypoxia AK1-deficient hearts, compared with the wild type, had a blunted AK-catalyzed phosphotransfer response, lowered intracellular ATP levels, increased Pi/ATP ratio, and suppressed generation of adenosine. Thus, although lack of AK1 phosphotransfer can be compensated in the absence of metabolic challenge, under hypoxia AK1-knockout hearts display compromised energetics and impaired cardioprotective signaling. This study, therefore, provides first direct evidence that AK1 is essential in maintaining myocardial energetic homeostasis, in particular under metabolic stress.

Original languageEnglish (US)
Pages (from-to)41424-41429
Number of pages6
JournalJournal of Biological Chemistry
Volume275
Issue number52
DOIs
StatePublished - Dec 29 2000

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Pucar, D., Janssen, E., Dzeja, P. P., Juranic, N., Macura, S., Wieringa, B., & Terzic, A. (2000). Compromised energetics in the adenylate kinase AK1 gene knockout heart under metabolic stress. Journal of Biological Chemistry, 275(52), 41424-41429. https://doi.org/10.1074/jbc.M007903200