title: Higd1a is a positive regulator of cytochrome c oxidase.
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.
authors.affiliation: Departments of Medical Biochemistry and Cardiovascular Medicine.
authors.forename: Takaharu
authors.initials: T
authors.lastname: Hayashi
authors.affiliation: Departments of Medical Biochemistry and Cardiovascular Medicine, takasima@cardiology.med.osaka-u.ac.jp asano@cardiology.med.osaka-u.ac.jp.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Asano
authors.affiliation: Departments of Medical Biochemistry and.
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Shintani
authors.affiliation: Graduate School of Pharmaceutical Science, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan;
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Aoyama
authors.affiliation: Cardiovascular Medicine.
authors.forename: Hidetaka
authors.initials: H
authors.lastname: Kioka
authors.affiliation: Departments of Medical Biochemistry and.
authors.forename: Osamu
authors.initials: O
authors.lastname: Tsukamoto
authors.affiliation: Department of Life Science, University of Hyogo, 3-2-1 Kouto, Kamigohri, Akoh, Hyogo 678-1297, Japan;
authors.forename: Masahide
authors.initials: M
authors.lastname: Hikita
authors.affiliation: Department of Life Science, University of Hyogo, 3-2-1 Kouto, Kamigohri, Akoh, Hyogo 678-1297, Japan;
authors.forename: Kyoko
authors.initials: K
authors.lastname: Shinzawa-Itoh
authors.affiliation: Center for Research Education, and.
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Takafuji
authors.affiliation: Departments of Medical Biochemistry and Cardiovascular Medicine.
authors.forename: Shuichiro
authors.initials: S
authors.lastname: Higo
authors.affiliation: Departments of Medical Biochemistry and.
authors.forename: Hisakazu
authors.initials: H
authors.lastname: Kato
authors.affiliation: Departments of Cell Biology and.
authors.forename: Satoru
authors.initials: S
authors.lastname: Yamazaki
authors.affiliation: Cardiovascular Medicine.
authors.forename: Ken
authors.initials: K
authors.lastname: Matsuoka
authors.affiliation: Clinical Research and Development, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka 565-8565, Japan;
authors.forename: Atsushi
authors.initials: A
authors.lastname: Nakano
authors.affiliation: Department of Cardiovascular Science and Technology, Kyoto Prefectural University School of Medicine, Kamigyo-ku, Kyoto 602-8566, Japan;
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Asanuma
authors.affiliation: Clinical Research and Development, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka 565-8565, Japan;
authors.forename: Masanori
authors.initials: M
authors.lastname: Asakura
authors.affiliation: Cardiovascular Medicine.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Minamino
authors.affiliation: Department of Child Neurology, National Center Hospital of Neurology and Psychiatry, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187-8502, Japan; and.
authors.forename: Yu-ichi
authors.initials: Y
authors.lastname: Goto
authors.affiliation: Department of Life Science, University of Hyogo, 3-2-1 Kouto, Kamigohri, Akoh, Hyogo 678-1297, Japan;
authors.forename: Takashi
authors.initials: T
authors.lastname: Ogura
authors.affiliation: Clinical Research and Development, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka 565-8565, Japan;
authors.forename: Masafumi
authors.initials: M
authors.lastname: Kitakaze
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, University of Tokyo, Tokyo 113-8656, Japan.
authors.forename: Issei
authors.initials: I
authors.lastname: Komuro
authors.affiliation: Cardiovascular Medicine.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Sakata
authors.affiliation: 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;
authors.forename: Tomitake
authors.initials: T
authors.lastname: Tsukihara
authors.affiliation: Department of Life Science, University of Hyogo, 3-2-1 Kouto, Kamigohri, Akoh, Hyogo 678-1297, Japan;
authors.forename: Shinya
authors.initials: S
authors.lastname: Yoshikawa
authors.affiliation: Departments of Medical Biochemistry and Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan; takasima@cardiology.med.osaka-u.ac.jp asano@cardiology.med.osaka-u.ac.jp.
authors.forename: Seiji
authors.initials: S
authors.lastname: Takashima
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D002417:Cattle; D003576:Electron Transport Complex IV / Q000737:chemistry / Q000378:metabolism*; D031541:Fluorescence Resonance Energy Transfer; D000860:Hypoxia / Q000201:enzymology / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000502:physiology*; D008928:Mitochondria / Q000201:enzymology; D010085:Oxidative Phosphorylation; D011487:Protein Conformation
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D000255:Adenosine Triphosphate; D003576:Electron Transport Complex IV
keywords: ATP; cytochrome c oxidase; oxidative phosphorylation; oxygen; resonance Raman spectroscopy