Hypoxia Inducible Factors Modulate Mitochondrial Oxygen Consumption and Transcriptional Regulation of Nuclear-Encoded Electron Transport Chain Genes

Biochemistry. 2015 Jun 23;54(24):3739-48. doi: 10.1021/bi5012892. Epub 2015 Jun 12.


Hypoxia inducible factor-1 (HIF1) is a stress-responsive nuclear transcription factor that is activated with a decrease in oxygen availability. HIF1 regulates the expression of genes involved in a cell's adaptation to hypoxic stress, including those with mitochondrial specific function. To gain a more comprehensive understanding of the role of HIF1 in mitochondrial homeostasis, we studied the link between hypoxia, HIF1 transactivation, and electron transport chain (ETC) function. We established immortalized mouse embryonic fibroblasts (MEFs) for HIF1α wild-type (WT) and null cells and tested whether HIF1α regulates mitochondrial respiration by modulating gene expressions of nuclear-encoded ETC components. High-throughput quantitative real-time polymerase chain reaction was performed to screen nuclear-encoded mitochondrial genes related to the ETC to identify those whose regulation was HIF1α-dependent. Our data suggest that HIF1α regulates transcription of cytochrome c oxidase (CcO) heart/muscle isoform 7a1 (Cox7a1) under hypoxia, where it is induced 1.5-2.5-fold, whereas Cox4i2 hypoxic induction was HIF1α-independent. We propose that adaptation to hypoxic stress of CcO as the main cellular oxygen consumer is mediated by induction of hypoxia-sensitive tissue-specific isoforms. We suggest that HIF1 plays a central role in maintaining homeostasis in cellular respiration during hypoxic stress via regulation of CcO activity.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Hypoxia
  • Cells, Cultured
  • Clone Cells
  • Electron Transport Complex IV / antagonists & inhibitors
  • Electron Transport Complex IV / genetics
  • Electron Transport Complex IV / metabolism*
  • Embryo, Mammalian / cytology
  • Embryo, Mammalian / metabolism
  • Enzyme Induction* / drug effects
  • Enzyme Inhibitors / pharmacology
  • Gene Expression Profiling
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Mice
  • Mice, Transgenic
  • Mitochondria / drug effects
  • Mitochondria / enzymology
  • Mitochondria / metabolism*
  • Oxidative Phosphorylation / drug effects
  • Oxygen Consumption* / drug effects
  • RNA, Messenger / metabolism
  • Recombinant Proteins / metabolism
  • Transcriptional Activation / drug effects


  • Enzyme Inhibitors
  • Hif1a protein, mouse
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • RNA, Messenger
  • Recombinant Proteins
  • Electron Transport Complex IV
  • cytochrome c oxidase subunit 7a1, mouse