Preconditioning-induced cytoprotection in hepatocytes requires Ca(2+)-dependent exocytosis of lysosomes

Rita Carini  1Roberta CastinoMaria Grazia De CesarisRoberta SplendoreMarina DémozEmanuele AlbanoCiro Isidoro



1 Laboratory of Pathology, Dipartimento di Scienze Mediche, Università del Piemonte Orientale A. Avogadro, via Solaroli 17, 28100 Novara, Italy.

PMID: 14970255

DOI: 10.1242/jcs.00923

J Cell Sci. 2004 Mar 1;117(Pt 7):1065-77. doi: 10.1242/jcs.00923. Epub 2004 Feb 17.



A short period of hypoxia reduces the cytotoxicity produced by a subsequent prolonged hypoxia in isolated hepatocytes. This phenomenon, termed hypoxic preconditioning, is mediated by the activation of adenosine A2A-receptor and is associated with the attenuation of cellular acidosis and Na+ overload normally occurring during hypoxia. Bafilomycin, an inhibitor of the vacuolar H+/ATPase, reverts the latter effects and abrogates the preconditioning-induced cytoprotection. Here we provide evidence that the acquisition of preconditioning-induced cytoprotection requires the fusion with plasma membrane and exocytosis of endosomal-lysosomal organelles. Poisons of the vesicular traffic, such as wortmannin and 3-methyladenine, which inhibit phosphatydilinositol 3-kinase, or cytochalasin D, which disassembles the actin cytoskeleton, prevented lysosome exocytosis and also abolished the preconditioning-associated protection from acidosis and necrosis provoked by hypoxia. Preconditioning was associated with the phosphatydilinositol 3-kinase-dependent increase of cytosolic [Ca2+]. Chelation of free cytosolic Ca2+ in preconditioned cells prevented lysosome exocytosis and the acquisition of cytoprotection. We conclude that lysosome-plasma membrane fusion is the mechanism through which hypoxic preconditioning allows hepatocytes to preserve the intracellular pH and survive hypoxic stress. This process is under the control of phosphatydilinositol 3-kinase and requires the integrity of the cytoskeleton and the rise of intracellular free calcium ions.

Clicca per votare questo articolo!
[Total: 0 Average: 0]
%d blogger hanno fatto clic su Mi Piace per questo: