Higd1a is a positive regulator of cytochrome c oxidase.
Proc Natl Acad Sci U S A
; 112(5): 1553-8, 2015 Feb 03.
Article
en En
| MEDLINE
| ID: mdl-25605899
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.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Complejo IV de Transporte de Electrones
/
Subunidad alfa del Factor 1 Inducible por Hipoxia
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Año:
2015
Tipo del documento:
Article