Details

Autor(en) / Beteiligte

• Sridharan, Vijayalakshmi
• Guichard, Jason
• Bailey, Rachel M
• Kasiganesan, Harinath
• Beeson, Craig
• Wright, Gary L

Titel

The prolyl hydroxylase oxygen-sensing pathway is cytoprotective and allows maintenance of mitochondrial membrane potential during metabolic inhibition

Ist Teil von

• American Journal of Physiology: Cell Physiology, 2007-02, Vol.292 (2), p.C719-C728

Ort / Verlag

United States: American Physiological Society

Erscheinungsjahr

2007

Quelle

MEDLINE

Beschreibungen/Notizen

• Department of Pharmaceutical Sciences, Medical University of South Carolina, Charleston, South Carolina Submitted 3 March 2006 ; accepted in final form 11 October 2006 The cellular oxygen sensor is a family of oxygen-dependent proline hydroxylase domain (PHD)-containing enzymes, whose reduction of activity initiate a hypoxic signal cascade. In these studies, prolyl hydroxylase inhibitors (PHIs) were used to activate the PHD-signaling pathway in cardiomyocytes. PHI-pretreatment led to the accumulation of glycogen and an increased maintenance of ATP levels in glucose-free medium containing cyanide. The addition of the glycolytic inhibitor 2-deoxy- D -glucose (2-DG) caused a decline of ATP levels that was indistinguishable between control and PHI-treated myocytes. Despite the comparable levels of ATP depletion, PHI-preconditioned myocytes remained significantly protected. As expected, mitochondrial membrane potential ( mito ) collapses in control myocytes during cyanide and 2-DG treatment and it fails to completely recover upon washout. In contrast, mito is partially maintained during metabolic inhibition and recovers completely on washout in PHI-preconditioned cells. Inclusion of rotenone, but not oligomycin, with cyanide and 2-DG was found to collapse mito in PHI-pretreated myocytes. Thus, continued complex I activity was implicated in the maintenance of mito in PHI-treated myocytes, whereas a role for the "reverse mode" operation of the F 1 F 0 -ATP synthase was ruled out. Further examination of mitochondrial function revealed that PHI treatment downregulated basal oxygen consumption to only 15% that of controls. Oxygen consumption rates, although initially lower in PHI-preconditioned myocytes, recovered completely upon removal of metabolic poisons, while reaching only 22% of preinsult levels in control myocytes. We conclude that PHD oxygen-sensing mechanism directs multiple compensatory changes in the cardiomyocyte, which include a low-respiring mitochondrial phenotype that is remarkably protected against metabolic insult. fumarate; hibernation; cardioprotection; anaplerotic Address for reprint requests and other correspondence: G. L. Wright, Dept. of Pharmaceutical Sciences, Medical Univ. of South Carolina, 280 Calhoun St., Charleston, SC 29425 (e-mail: wrightgl{at}musc.edu )