Calcium-Regulated Mitochondria Remodeling by Myo19 is Required for Filopodia Tip-Extension

Mitochondria are highly adaptable organelles that change their shape, distribution, and movement to meet cellular needs. We investigate how EGF stimulation remodels mitochondrial behavior in human A431 carcinoma cells, where EGF suppresses proliferation but enhances calcium signaling and cell motility. EGF triggers mitochondrial fission, resulting in smaller, more mobile mitochondria that relocate to the tips of newly formed filopodia. Mitochondrial transport involves Kif5B (microtubule-based) and Myo19 (actin-based) motor proteins, which are regulated differently by calcium. EGF stimulation increases cytosolic calcium, weakening Kif5B-mediated transport and making Myo19 the primary transporter. Mitochondrial calcium uptake through the MCU channel is essential for redistribution, shape changes, and filopodia extension. Disrupting mitochondrial fission or calcium buffering impairs mitochondrial motility and the formation of filopodia. High-resolution imaging reveals the coordinated transport of mitochondria, involving fission, motor switching, and localized calcium signaling. We provide insights into how mitochondrial transport supports actin remodeling and protrusive activity, with implications for cell migration and therapies targeting mitochondrial-cytoskeletal interactions. HIGHLIGHTSO_LIEGF stimulation remodels the morphology of the mitochondrial network C_LIO_LIKif5B and Myo19 are required for mitochondrial motility C_LIO_LIMitochondria display two different velocities depending on the cell region C_LIO_LICalcium homeostasis contributes to mitochondrial network remodeling C_LI eTOC BLURBCell powerhouses called mitochondria can change shape and move within cells along tracks called the cytoskeleton. Stimulation of cells by stressors, such as growth factors, can generate signals that cause mitochondria to migrate to the cell edges using molecular motors. Importantly, this movement enables cells to form finger-like projections, providing the energy necessary for cell migration.