Mitochondrial Ca2+uptake controls actin cytoskeleton dynamics during cell migration.
Intracellular Ca2+signaling regulates cell migration by acting on cytoskeleton architecture, cell directionality and focal adhesions dynamics. In migrating cells, cytosolic Ca2+pool and Ca2+pulses are described as key components of these effects. Whereas the role of the mitochondrial calcium homeostasis and the Mitochondria Cacium Uniporter (MCU) in cell migration were recently highlighted in vivo using the zebrafish model, their implication in actin cystokeleton dynamics and cell migration in mammals is not totally characterized. Here, we show that mcu silencing in two human cell lines compromises their migration capacities. This phenotype is characterized by actin cytoskeleton stiffness, a cell polarization loss and an impairment of the focal adhesion proteins dynamics. At the molecular level, these effects appear to be mediated by the reduction of the ER and cytosolic Ca2+pools, which leads to a decrease in Rho-GTPases, RhoA and Rac1, and Ca2+-dependent Calpain activites, but seem to be independent of intracellular ATP levels. Together, this study highlights the fundamental and evolutionary conserved role of the mitochondrial Ca2+homeostasis in cytoskeleton dynamics and cell migration.
Medical Research Council, Mitochondrial Biology Unit, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, UK.
Julien
J
Prudent
Université de Lyon, Centre de recherche en cancérologie de Lyon, U1052 INSERM, UMR CNRS 5286, Université Lyon I, Centre Léon Bérard, 28 rue Laennec, 69008 Lyon, France.
Nikolay
N
Popgeorgiev
Université de Lyon, Centre de recherche en cancérologie de Lyon, U1052 INSERM, UMR CNRS 5286, Université Lyon I, Centre Léon Bérard, 28 rue Laennec, 69008 Lyon, France.
Rudy
R
Gadet
Université de Lyon, Centre de recherche en cancérologie de Lyon, U1052 INSERM, UMR CNRS 5286, Université Lyon I, Centre Léon Bérard, 28 rue Laennec, 69008 Lyon, France.
Mathieu
M
Deygas
Université de Lyon, Centre de recherche en cancérologie de Lyon, U1052 INSERM, UMR CNRS 5286, Université Lyon I, Centre Léon Bérard, 28 rue Laennec, 69008 Lyon, France.
Ruth
R
Rimokh
Université de Lyon, Centre de recherche en cancérologie de Lyon, U1052 INSERM, UMR CNRS 5286, Université Lyon I, Centre Léon Bérard, 28 rue Laennec, 69008 Lyon, France.|Hospices civils de Lyon, Laboratoire d'anatomie et cytologie pathologiques, Centre Hospitalier Lyon Sud, Chemin du Grand Revoyet, 69495 Pierre Bénite, France.
Germain
G
Gillet
D008841:Actin Cytoskeleton / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002465:Cell Movement; D016764:Cell Polarity; D015536:Down-Regulation; D022001:Focal Adhesions; D008928:Mitochondria / Q000378:metabolism*; D023421:Models, Animal; D015027:Zebrafish
D002118:Calcium