Graduate School of Frontier Biosciences, Osaka University

Japanese

Higd1a is a positive regulator of cytochrome c oxidase.

Journal Proc Natl Acad Sci USA 112, 1553–1558 (2015)
Authors Hayashi T. (1), Asano Y. (2), Shintani Y. (3), Aoyama H. (4), Kioka H. (5), Tsukamoto O. (3), Hikita M. (6), Shinzawa-Itoh K. (6), Takafuji K. (7), Higo S. (1), Kato H. (3), Yamazaki S. (8), Matsuoka K. (5), Nakano A. (9), Asanuma H. (10), Asakura M. (9), Minamino T. (5), Goto Y. (11), Ogura T. (6), Kitakaze M. (9), Komuro I. (12), Sakata Y. (5), Tsukihara T. (13), Yoshikawa S. (6), Takashima S. (14)

  1. Departments of Medical Biochemistry and Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
  2. Departments of Medical Biochemistry and Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
  3. Departments of Medical Biochemistry, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
  4. Graduate School of Pharmaceutical Science, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
  5. Cardiovascular Medicine, University of Hyogo, 3-2-1 Kouto, Kamigohri, Akoh, Hyogo 678-1297, Japan
  6. Department of Life Science, University of Hyogo, 3-2-1 Kouto, Kamigohri, Akoh, Hyogo 678-1297, Japan
  7. Center for Research Education, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka 565-8565, Japan
  8. Departments of Cell Biology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka 565-8565, Japan
  9. Clinical Research and Development, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka 565-8565, Japan
  10. Department of Cardiovascular Science and Technology, Kyoto Prefectural University School of Medicine, Kamigyo-ku, Kyoto 602-8566, Japan
  11. Department of Child Neurology, National Center Hospital of Neurology and Psychiatry, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187-8502, Japan
  12. Department of Cardiovascular Medicine, Graduate School of Medicine, University of Tokyo, Tokyo 113-8656, Japan
  13. Department of Life Science, University of Hyogo, 3-2-1 Kouto, Kamigohri, Akoh, Hyogo 678-1297, Japan; Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan
  14. Departments of Medical Biochemistry and Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan
Title Higd1a is a positive regulator of cytochrome c oxidase.
PubMed 25605899
Laboratory Department of Medical Biochemistry 〈Prof. Takashima〉
Description 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.