期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 112, 期 5, 页码 1553-1558出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1419767112
关键词
cytochrome c oxidase; oxidative phosphorylation; resonance Raman spectroscopy; ATP; oxygen
资金
- Japan Society for the Promotion of Science
- Ministry of Health, Labor, and Welfare-Japan
- Ministry of Education, Culture, Sports, Science, and Technology-Japan
- Takeda Science Foundation,
- Japan Heart Foundation
- Japan Cardiovascular Research Foundation
- Japan Intractable Diseases Research Foundation
- Japan Foundation of Applied Enzymology
- Japan Medical Association
- Uehara Memorial Foundation
- Mochida Memorial Foundation
- Banyu Foundation
- Naito Foundation
- Inoue Foundation for Science, Osaka Medical Research foundation for intractable diseases
- Ichiro Kanehara Foundation
- Showa Houkoukai
- Grants-in-Aid for Scientific Research [24591096, 25109540, 26670402, 26291033, 26104532, 26253049, 25461119] Funding Source: KAKEN
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.
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