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This Article Full Text Full Text (PDF) All Versions of this Article: 294/6/H2507    most recent 00168.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Takahashi, E. Search for Related Content PubMed PubMed Citation Articles by Takahashi, E.

Anoxic cell core can promote necrotic cell death in cardiomyocytes at physiological extracellular PO₂

General Medical Education Center and Department of Physiology, Yamagata University School of Medicine, Yamagata, Japan

Submitted 15 February 2008 ; accepted in final form 14 April 2008

The physical law of diffusion imposes O₂ concentration gradients from the plasma membrane to the center of the cell. The present study was undertaken to determine how such intracellular radial gradients of O₂ affect the fate of isolated single cardiomyocytes. In single rat cardiomyocytes, mitochondrial respiration was moderately elevated by an oxidative phosphorylation uncoupler to augment the intracellular O₂ gradient. At physiological extracellular O₂ levels (2–5%), decreases in myoglobin O₂ saturation and increases in NADH fluorescence at the center of the cell were imaged (anoxic cell core) while the mitochondrial membrane potential (_m) and ATP levels at the anoxic cell core were relatively sustained. In contrast, treatment with 0.5 mM iodoacetamide (IA) to inhibit creatine kinase (CK) resulted in depletion of both _m and ATP at the anoxic cell core. Even at normal extracellular PO₂, actively respiring cardiomyocytes developed rigor contracture followed by necrotic cell death. Furthermore, such rigor was remarkably accelerated by IA, whereas cell injury was perfectly rescued by mitochondrial F₁F_o inhibition by oligomycin. These results suggest that increases in radial gradients of O₂ potentially promote cell death through the reverse action of F₁F_o in mitochondria located at the anoxic cell core. However, in the intact cardiomyocyte, the CK-mediated energy flux from the subsarcolemmal space may sustain _m at the cell core, thus avoiding uncontrolled consumption of ATP that can lead to necrotic cell death. Mitochondria at the anoxic core can cause necrotic cell death in cardiomyocytes at physiological extracellular PO₂.

necrosis; mitochondria; hypoxia; creatine kinase; energy shuttle