Characterization of the effect of the mitochondrial protein Hint2 on intracellular Ca(2+) dynamics.
Biophys J
; 105(5): 1268-75, 2013 Sep 03.
Article
em En
| MEDLINE
| ID: mdl-24010670
ABSTRACT
Hint2, one of the five members of the superfamily of the histidine triad AMP-lysine hydrolase proteins, is expressed in mitochondria of various cell types. In human adrenocarcinoma cells, Hint2 modulates Ca(2+) handling by mitochondria. As Hint2 is highly expressed in hepatocytes, we investigated if this protein affects Ca(2+) dynamics in this cell type. We found that in hepatocytes isolated from Hint2(-/-) mice, the frequency of Ca(2+) oscillations induced by 1 µM noradrenaline was 150% higher than in the wild-type. Using spectrophotometry, we analyzed the rates of Ca(2+) pumping in suspensions of mitochondria prepared from hepatocytes of either wild-type or Hint2(-/-) mice; we found that Hint2 accelerates Ca(2+) pumping into mitochondria. We then resorted to computational modeling to elucidate the possible molecular target of Hint2 that could explain both observations. On the basis of a detailed model for mitochondrial metabolism proposed in another study, we identified the respiratory chain as the most probable target of Hint2. We then used the model to predict that the absence of Hint2 leads to a premature opening of the mitochondrial permeability transition pore in response to repetitive additions of Ca(2+) in suspensions of mitochondria. This prediction was then confirmed experimentally.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article