Mitochondrial Ca2+ uptake controls actin cytoskeleton dynamics during cell migration

Abstract

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.

MCU Up‐regulation contributes to myocardial ischemia‐reperfusion Injury through calpain/OPA‐1–mediated mitochondrial fusion/mitophagy Inhibition

“…and participates in I/R injury through the mechanism of MCU-Ca 2+ overload-mPTP opening. 8,19,20 In the present study, mito- 9 Previous studies have shown that calpain activation can cause cardiac dysfunction and apoptosis through a variety of signalling pathways. 23 In mitochondria, activated calpain cleaves and modifies apoptosis-inducing factor in mitochondria to release it from mitochondria to cytoplasm and initiate apoptosis.…”

Oncogenic KRAS suppresses store-operated Ca 2+ entry and I CRAC through ERK pathway-dependent remodelling of STIM expression in colorectal cancer cell lines

“…Of particular note, Ca 2+ signals are necessary to sustain the cell cycle at specific checkpoints such as G 1 /S and G 2 /M transitions [20,21] and mitochondrial Ca 2+ overload is a key event in activating the apoptotic cascade [22]. Cell migration and invasion associated with tumour metastasis are also regulated by Ca 2+ [23–26]. …”

Mitochondria tether to Focal Adhesions during cell migration and regulate their size

“…Mitochondria move to the leading edge during migration. In both breast and ovarian cancer cells, mitochondria infiltrate into the leading edge lamellipodia [14,15,20]. To determine whether or not this was the case in non-transformed cells, we used live cell microscopy to image mitochondria in freely migrating NIH3T3 mouse fibroblasts (Fig 1a, Supplementary Video 1).…”

“…Previous reports indicate that regulation of calcium flux via the Mitochondrial Calcium Uniporter (MCU) and energy levels via the AMP-activated protein kinase (AMPK) are two pathways through which mitochondria affect migration [14,15]. However, it is unknown what migratory structures in lamellipodia mitochondria might be interacting with.…”

“…Dysregulated migration is often associated with cancer development and metastatic progression [17]. Fragmented mitochondria are found to infiltrate the leading edge of breast and ovarian cancer cell during migration [14,15]. Inhibition of either mitochondrial ATP generation [14] or Ca 2+ uptake through silencing of the Mitochondrial Calcium Uniporter (MCU) [15] inhibits motility.…”