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. 2007 Jan 26;25(2):193-205.
doi: 10.1016/j.molcel.2006.12.009.

Control of macroautophagy by calcium, calmodulin-dependent kinase kinase-beta, and Bcl-2

Maria Høyer-Hansen  1 , Lone Bastholm, Piotr Szyniarowski, Michelangelo Campanella, György Szabadkai, Thomas Farkas, Katiuscia Bianchi, Nicole Fehrenbacher, Folmer Elling, Rosario Rizzuto, Ida Stenfeldt Mathiasen, Marja Jäättelä
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Free article

Control of macroautophagy by calcium, calmodulin-dependent kinase kinase-beta, and Bcl-2

Maria Høyer-Hansen et al. Mol Cell. .
Free article

Abstract

Macroautophagy is an evolutionary conserved lysosomal pathway involved in the turnover of cellular macromolecules and organelles. In spite of its essential role in tissue homeostasis, the molecular mechanisms regulating mammalian macroautophagy are poorly understood. Here, we demonstrate that a rise in the free cytosolic calcium ([Ca(2+)](c)) is a potent inducer of macroautophagy. Various Ca(2+) mobilizing agents (vitamin D(3) compounds, ionomycin, ATP, and thapsigargin) inhibit the activity of mammalian target of rapamycin, a negative regulator of macroautophagy, and induce massive accumulation of autophagosomes in a Beclin 1- and Atg7-dependent manner. This process is mediated by Ca(2+)/calmodulin-dependent kinase kinase-beta and AMP-activated protein kinase and inhibited by ectopic Bcl-2 located in the endoplasmatic reticulum (ER), where it lowers the [Ca(2+)](ER) and attenuates agonist-induced Ca(2+) fluxes. Thus, an increase in the [Ca(2+)](c) serves as a potent inducer of macroautophagy and as a target for the antiautophagy action of ER-located Bcl-2.

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