Higd1a is a positive regulator of cytochrome c oxidase.
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.
['Hayashi|Takaharu|T|', 'Asano|Yoshihiro|Y|', 'Shintani|Yasunori|Y|', 'Aoyama|Hiroshi|H|', 'Kioka|Hidetaka|H|', 'Tsukamoto|Osamu|O|', 'Hikita|Masahide|M|', 'Shinzawa-Itoh|Kyoko|K|', 'Takafuji|Kazuaki|K|', 'Higo|Shuichiro|S|', 'Kato|Hisakazu|H|', 'Yamazaki|Satoru|S|', 'Matsuoka|Ken|K|', 'Nakano|Atsushi|A|', 'Asanuma|Hiroshi|H|', 'Asakura|Masanori|M|', 'Minamino|Tetsuo|T|', 'Goto|Yu-ichi|Y|', 'Ogura|Takashi|T|', 'Kitakaze|Masafumi|M|', 'Komuro|Issei|I|', 'Sakata|Yasushi|Y|', 'Tsukihara|Tomitake|T|', 'Yoshikawa|Shinya|S|', 'Takashima|Seiji|S|']
D000255:Adenosine Triphosphate D000818:Animals D002417:Cattle D003576:Electron Transport Complex IV D031541:Fluorescence Resonance Energy Transfer D000860:Hypoxia D051795:Hypoxia-Inducible Factor 1, alpha Subunit D008928:Mitochondria D010085:Oxidative Phosphorylation D011487:Protein Conformation
cytochrome c oxidase oxygen ATP oxidative phosphorylation resonance Raman spectroscopy