The survival effect of mitochondrial Higd-1a is associated with suppression of cytochrome C release and prevention of caspase activation

Biochim Biophys Acta. 2011 Dec;1813(12):2088-98. doi: 10.1016/j.bbamcr.2011.07.017. Epub 2011 Aug 10.


Higd-1a (hypoxia induced gene domain family-1a) is a mitochondrial inner membrane protein with a conformation of N-terminal outside-C-terminal outside and loop inside. There are four Higd genes, Higd-1a, -1b, -1c and -2a, in the mouse. Higd-1a and -2a are expressed primarily in the brain, heart, kidney and leukocytes. HIF (hypoxia-inducible factor) overexpression induced the endogenous expression and promoter activity of Higd-1a. Mutation of the HRE (hypoxia-response element) site at -32bp in the Higd-1a promoter reduced the promoter activity, suggesting that transcription of Higd-1a is regulated by binding of the transcription factor HIF to the HRE. Higd-1a promoted cell survival under hypoxia. RAW264.7 cells stably transfected with Higd-1a underwent less apoptosis than control cells in a hypoxic condition, and hypoxia-induced apoptosis was strongly enhanced when endogenous Higd-1a was silenced by siRNA. The survival effect of Higd-1a was completely abolished by deletion of the 26 N-terminal amino acids, and we showed that Higd-1a increased survival by inhibiting cytochrome C release and reducing the activities of caspases. However, expression of Bcl-2, Bax, Bad, and BNIP3 and translocation of AIF were unaffected under the same conditions. Higd-2a also enhanced cell survival under hypoxia. Cells transfected with Higd-2a underwent less apoptosis than control cells in hypoxic conditions, and hypoxia-induced apoptosis increased when endogenous Higd-2a was depleted. Together these observations indicate that Higd-1a is induced by hypoxia in a HIF-dependent manner and its anti-apoptotic effect results from inhibiting cytochrome C release and reducing caspase activities.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / metabolism
  • Adenocarcinoma / pathology
  • Amino Acid Sequence
  • Animals
  • Apoptosis*
  • Blotting, Western
  • Caspases / metabolism*
  • Cell Hypoxia
  • Cells, Cultured
  • Cytochromes c / metabolism*
  • DNA, Mitochondrial / genetics
  • Enzyme Activation
  • Flow Cytometry
  • HeLa Cells
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Intracellular Signaling Peptides and Proteins
  • Macrophages / cytology
  • Macrophages / metabolism
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Mitochondria / genetics
  • Mitochondria / metabolism*
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism*
  • Molecular Sequence Data
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology
  • RNA, Messenger / genetics
  • Real-Time Polymerase Chain Reaction
  • Response Elements / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sequence Homology, Amino Acid


  • DNA, Mitochondrial
  • Hif1a protein, mouse
  • Hig1 protein, mouse
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Mitochondrial Proteins
  • RNA, Messenger
  • Cytochromes c
  • Caspases