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Activation of the PHD oxygen‐sensing pathway induces a low‐respiring, protected mitochondrial phenotype
Author(s) -
Wright Gary L.,
Sridharan Vijayalakshmi,
Guichard Jason,
Beeson Craig C.
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.6.a924-a
Subject(s) - oligomycin , mitochondrion , glycolysis , biochemistry , chemistry , microbiology and biotechnology , myocyte , cyanide , oxygen , cytosol , biology , biophysics , enzyme , atpase , organic chemistry , inorganic chemistry
In these studies, prolyl hydroxylase inhibitors (PHIs) were used to activate the proline hydroxylase‐domain containing (PHD) oxygen‐sensing pathway in cardiomyocytes. Addition of cyanide and the glycolytic inhibitor 2‐deoxy‐D‐glucose (2‐DG) caused, as expected, the collapse of mitochondrial membrane potential (ΔΨ mito ) in control cells with only partial recovery upon washout. In contrast, ΔΨ mito is partially maintained during metabolic inhibition and recovers completely upon washout in PHI‐preconditioned cells. Inclusion of rotenone, but not oligomycin, with cyanide and 2‐DG was found to collapse ΔΨ mito in PHI‐pretreated myocytes. Thus, continued complex I activity was implicated in the maintenance of ΔΨ mito in PHI‐treated myocytes, while a role for the ‘reverse mode’ operation of the F 1 Fo‐ATP synthase was ruled out. Evidence of fumarate to succinate reduction by complex II in the PHI‐treated, but not control myocytes, provides an explanation for the apparent finding of ‘anaerobic’ complex I function. Finally we find that PHI‐treatment downregulates basal O 2 ‐consumption to only ~15% that of controls. Remarkably, addition of DNP, an uncoupler, does not increase O 2 ‐consumption rates in PHI‐treated myocytes. We conclude that PHD pathway directs mechanisms that allow anaerobic complex I function and that lead to a low‐respiring mitochondrial phenotype that is protected against metabolic insult.