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.
journal_name
Biophys Jjournal_title
Biophysical journalauthors
Ndiaye D,Collado-Hilly M,Martin J,Prigent S,Dufour JF,Combettes L,Dupont Gdoi
10.1016/j.bpj.2013.06.048subject
Has Abstractpub_date
2013-09-03 00:00:00pages
1268-75issue
5eissn
0006-3495issn
1542-0086pii
S0006-3495(13)00795-9journal_volume
105pub_type
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