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Hypoxic inhibition of mitochondrial oxygen consumption depends on HIF‐1α
Author(s) -
Mairbaurl Heimo,
Baloglu Emel,
Zhang Ying
Publication year - 2016
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.30.1_supplement.1279.10
Subject(s) - ampk , hypoxia (environmental) , mitochondrion , microbiology and biotechnology , endocrinology , medicine , downregulation and upregulation , protein kinase a , oxidative phosphorylation , amp activated protein kinase , stimulation , chemistry , mitochondrial ros , mitochondrial dna , biology , phosphorylation , oxygen , biochemistry , gene , organic chemistry
The AMP‐activated protein kinase (AMPK) couples cellular energy demand and ATP production by increasing PGC‐1α‐dependent expression of mitochondrial proteins. Hypoxia decreases mitochondrial activity. Here we tested the hypothesis that stimulation of AMPK, which indicates increased metabolic demand, blunts the impaired mitochondrial function in hypoxia to prevent functional impairment of cardiomyocytes. H‐10 cardiomyocytes were treated with AICAR to stimulate AMPK in normoxia and hypoxia (1.5 % O 2 ). AICAR, hypoxia, and their combination increased phosphorylated AMPK indicating its stimulation. AICAR induced a 3x increase in mitochondrial oxygen consumption (JO 2 ), whereas hypoxia decreased JO 2 (−20%) and prevented the AICAR‐induced increase. Hypoxia did not prevent the AICAR‐induced increase in pyruvate dehydrogenase (PDH) activity despite increased PDK mRNA expression. The HIF‐dependent genes GAPD (1.5x) and BNIP3 (4x) were increased in hypoxia, also in the presence of AICAR. Silencing HIF‐1α prevented the hypoxia‐induced inhibition of mitochondrial respiration in control and AICAR‐treated cells and significantly reduces upregulation of HIF‐dependent genes. These results indicate that hypoxia prevents the AMP‐ and AMPK‐dependent stimulation of mitochondrial metabolism by HIF‐1α dependent mechanisms thus disproving our hypothesis. The inhibition by hypoxia seems to be caused by decreasing the expression of enzymes of the electron transfer chain by blocking signaling downstream of AMPK rather than by decreasing PDH‐mediated substrate flux into mitochondria. Together this indicates that hypoxia decreases cardiomyocyte oxidative metabolism despite increased metabolic demand. Support or Funding Information DFG Ma‐1503/29‐1