Hayashi, T., Asano, Y., Shintani, Y., Aoyama, H., Kioka, H., Tsukamoto, O., … Takashima, S.
Departments of Medical Biochemistry and Cardiovascular Medicine, Centre for Research Education, and Graduate School of Pharmaceutical Science, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan; 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; Departments of Cell Biology and Clinical Research and Development, National Cerebral and Cardiovascular Centre Research Institute, Suita, Osaka 565-8565, Japan; Department of Cardiovascular Science and Technology, Kyoto Prefectural University School of Medicine, Kamigyo-ku, Kyoto 602-8566, Japan; Department of Child Neurology, National Centre Hospital of Neurology and Psychiatry, National Centre of Neurology and Psychiatry, Kodaira, Tokyo 187-8502, Japan; and Department of Cardiovascular Medicine, Graduate School of Medicine, University of Tokyo, Tokyo 113-8656, Japan.
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 centre 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.
… “Cells were illuminated using the CoolLED pE-1 excitation system (CoolLED) with a wavelength of 425 nm.”…
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