Mapping hypoxia-induced bioenergetic rearrangements and metabolic signaling by18O-assisted31P NMR and1H NMR spectroscopy

This study shows specific benefits stemming from the combined use of highresolution 31P and 1H NMR spectroscopy that accompanies 18O analysis

Darko Pucar


Scholarcy highlights

  • Oxygen deficiency associated with hypoxic or ischemic stress in heart muscle disrupts mitochondrial oxidative phosphorylation compromising ATP production and associated ATPdependent cellular processes
  • In the well-oxygenated heart, transfer of high-energy phosphoryls between sites of ATP production and consumption is facilitated by the creatine kinase and adenylate kinase system, with creatine kinase phosphotransfer serving a dominant role
  • Reduction in the CK/AK flux ratio, from 6.5 ± 0.4 in normoxia to 0.8 ± 0.2 in hypoxia, indicates rearrangement in phosphotransfer signaling with adenylate kinase playing a major role in supporting heart energetics under hypoxic stress
  • 18O-assisted 31P NMR with 1H NMR analysis mapped the bioenergetic dynamics of the myocardium under hypoxic stress
  • While in normoxia the majority of high-energy phosphoryl transfer proceeds through the creatine kinase system with a relatively minor contribution by AK, under hypoxia the rapid decline in CK-mediated phosphotransfer was associated with an apparently adaptive up-regulation of AK-catalyzed flux, and the generation of adenosine monophosphate, inosine monophosphate and adenosine, molecules involved in cardioprotective signaling
  • 31P and 1H NMR spectral analysis revealed that scavenging of NADH and H+, by α-glycerophosphate dehydrogenase and lactate dehydrogenase, contributing to maintained glycolysis, which along with AK phosphotransfer supports cardiac bioenergetics under hypoxia
  • In a single experiment one can measure creatine kinase, adenylate kinase and glycolytic phosphotransfer fluxes, as well as ATP production, consumption and total turnover rates, providing a comprehensive analysis of dynamic alterations in the energetic system of an intact cell

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