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Hypoxic Adaptation by a Unique Mechanism of Reprogramming Mitochondrial Metabolism
Author(s) -
Tessman Robert T,
Chavan Hementkumar,
Du Gouqing,
Sun Daxi,
Schuetz John,
Krishnamurthy Partha
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.1100.9
Subject(s) - hypoxia (environmental) , reprogramming , downregulation and upregulation , mitochondrion , microbiology and biotechnology , biology , transcription factor , ectopic expression , hypoxia inducible factors , transfection , chemistry , cancer research , gene , biochemistry , oxygen , organic chemistry
Hypoxia plays critical roles in the pathobiology of heart disease, cancer, stroke, and chronic lung disease, which are responsible for 60% of deaths in the United States. Evidence suggests that hypoxic survival often requires reprogramming of mitochondrial basal metabolism. However, our understanding of the fundamental mechanisms that regulate mitochondrial metabolism are still incomplete. During our studies evaluating the physiological significance of the mitochondrial transporter ABCB6, we uncovered a novel pathway in which loss of ABCB6 expression shifts the balance between mitochondrial respiration and glycolysis because ABCB6 expression decreased mitochondrial respiratory rate and increased glycolysis rate. More importantly, we found that the major transcriptional sensor of oxygen hypoxia‐inducible factor (HIF) was involved in the activation of Abcb6 expression under hypoxic conditions. Further, ABCB6 promoter contains hypoxia response (HRE) elements. These HREs are functional because the promoter is activated by the hypoxia mimetic, desferoxamine as well as directly by co‐transfected HIF1‐alpha. Moreover, in cells with a defective HIF, ABCB6 expression is not upregulated by hypoxia. Finally, ectopic overexpression of ABCB6 reveals that ABCB6 protects cells from the cytotoxicity induced by hypoxia. These studies reveal that ABCB6, a mitochondrial ABC transporter, is regulated by hypoxia and the major hypoxia transcription factor HIF1‐alpha. This upregulation by hypoxia is compatible with ABCB6 overexpression providing a survival advantage under hypoxic conditions. Support or Funding Information P20RR021940‐7 T32ES007079