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Rôle des mitochondries dans la régulation des oscillations de calcium des hépatocytes : approches expérimentale et computationnelle

Abstract : Calcium signaling plays a crucial role in cell response to external stimuli. These last years, the progress of the microsocopy techniques allowed demonstrate that spatio-temporal organisation of the calcium signal is fundamental for cell physiology. This spatio-temporal organization is characterized by the observation of calcium oscillations whose frequency varies according to the stimulus. For many cell types in particular hepatocytes, calcium oscillations amplitude and frequency are regular and finely regulated. The large range of actors involved in this regulation explains the complexity of studying this process. This explains why the calcium oscillations studies are one of the area in which the experimental approach is commonly associated with computational approaches.Among all the elements participating in the regulation of calcium signaling, mitochondria that have been thought for many years to play a passive role may have a greater role. Indeed it has been shown that mitochondria are able to accumulate actively calcium from the endoplasmic reticulum.Our goal was to study the importance of mitochondria in calcium oscillations regulation in hepatocytes and to elaborate a model based on these experimental results. For that purpose we choose to change the calcium uptake by mitochondria using techniques that didn’t kill them. We used a protein that alters directly mitochondrial calcium uptake (Hint 2), and a protein involved in the interaction between endoplasmic reticulum and mitochondria (R-1).Our experimental and computational results show that HINT 2 enhances the electron transport chain activity, which lead to faster mitochondrial calcium uptake and faster calcium oscillations in the cytosol of hepatocytes. The model allows us not only to reproduce experimental data but also to successfully predict that the loss of HINT 2 lead the mitochondria to be more sensitive to the mitochondrial transition pore opening (mPTP).We also demonstrate that R-1 doesn’t change mitochondrial calcium uptake, but its over expression lead to a higher calcium concentration in resting cells. In the light of our results, this higher calcium concentration seems to be the result of R-1 interaction with ATPase pump SERCA 2.Our results allowed us to show not only the role of mitochondria in the regulation of hepatocytes calcium oscillations by HINT 2, but also the link between R-1 over expression and a higher calcium concentration in the cytosol of HepG2 cells.
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Dieynaba Ndiaye. Rôle des mitochondries dans la régulation des oscillations de calcium des hépatocytes : approches expérimentale et computationnelle. Sciences agricoles. Université Paris Sud - Paris XI; Université libre de Bruxelles (1970-..), 2013. Français. ⟨NNT : 2013PA11T023⟩. ⟨tel-00998301⟩

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