Higd1a is a positive regulator of cytochrome c oxidase

Proc Natl Acad Sci U S A. 2015 Feb 3;112(5):1553-8. doi: 10.1073/pnas.1419767112. Epub 2015 Jan 20.

Abstract

Cytochrome c oxidase (CcO) is the only enzyme that uses oxygen to produce a proton gradient for ATP production during mitochondrial oxidative phosphorylation. Although CcO activity increases in response to hypoxia, the underlying regulatory mechanism remains elusive. By screening for hypoxia-inducible genes in cardiomyocytes, we identified hypoxia inducible domain family, member 1A (Higd1a) as a positive regulator of CcO. Recombinant Higd1a directly integrated into highly purified CcO and increased its activity. Resonance Raman analysis revealed that Higd1a caused structural changes around heme a, the active center that drives the proton pump. Using a mitochondria-targeted ATP biosensor, we showed that knockdown of endogenous Higd1a reduced oxygen consumption and subsequent mitochondrial ATP synthesis, leading to increased cell death in response to hypoxia; all of these phenotypes were rescued by exogenous Higd1a. These results suggest that Higd1a is a previously unidentified regulatory component of CcO, and represents a therapeutic target for diseases associated with reduced CcO activity.

Keywords: ATP; cytochrome c oxidase; oxidative phosphorylation; oxygen; resonance Raman spectroscopy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / biosynthesis
  • Animals
  • Cattle
  • Electron Transport Complex IV / chemistry
  • Electron Transport Complex IV / metabolism*
  • Fluorescence Resonance Energy Transfer
  • Hypoxia / enzymology
  • Hypoxia / metabolism
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / physiology*
  • Mitochondria / enzymology
  • Oxidative Phosphorylation
  • Protein Conformation

Substances

  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Adenosine Triphosphate
  • Electron Transport Complex IV