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CELLULAR AND MITOCHONDRIAL METABOLISM

O₂-sensing signal cascade: clamping of O₂ respiration, reduced ATP utilization, and inducible fumarate respiration

Department of Pharmaceutical Sciences, Medical University of South Carolina, Charleston, South Carolina

Submitted 5 October 2007 ; accepted in final form 1 May 2008

These studies explore the consequences of activating the prolyl hydroxylase (PHD) O₂-sensing pathway in spontaneously twitching neonatal cardiomyocytes. Full activation of the PHD pathway was achieved using the broad-spectrum PHD inhibitor (PHI) dimethyloxaloylglycine (DMOG). PHI treatment of cardiomyocytes caused an 85% decrease in O₂ consumption and a 300% increase in lactic acid production under basal conditions. This indicates a 75% decrease in ATP turnover rate, inasmuch as the increased ATP generation by glycolysis is inadequate to compensate for the lower respiration. To determine the extent to which decreased ATP turnover underlies the suppressed O₂ consumption, mitochondria were uncoupled with 2,4-dinitrophenol. We were surprised to find that 2,4-dinitrophenol failed to increase O₂ consumption by PHI-treated cells, indicating that electron transport chain activity, rather than ATP turnover rate, limits respiration in PHI-treated cardiomyocytes. Silencing of hypoxia-inducible factor-1 (HIF-1) expression restored the ability of uncoupled PHI-treated myocytes to increase O₂ consumption; however, basal O₂ uptake rates remained low because of the unabated suppression of cellular ATP consumption. Thus it appears that respiration is actively "clamped" through an HIF-dependent mechanism, whereas HIF-independent mechanisms are responsible for downregulation of ATP consumption. In addition, we find that PHD pathway activation enables mitochondria to utilize fumarate as a terminal electron acceptor when cytochrome c oxidase is inactive. The source of fumarate for this unusual respiration is derived from aspartate via the purine nucleotide cycle. In sum, these studies show that the O₂-sensing pathway is sufficient to actively "clamp" O₂ consumption and independently suppress cellular ATP consumption. The PHD pathway also enables the mitochondria to utilize fumarate for respiration.

mitochondrial membrane potential; hibernation; cardioprotection

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