A major route for influx of calcium ions into neurons uses the STIM-Orai1 voltage-independent channel. Once cytosolic calcium ([Ca2+]i) elevates, it activates mitochondrial and endoplasmic calcium stores, to affect downstream molecular pathways. In the present study we employed a novel drug, Carbonyl Cyanide Chlorophenylhydrazone (CCCP), a mitochondrial uncoupler, to explore the role of mitochondria in cultured neuronal morphology. CCCP caused a sustained elevation of [Ca2+]i and, quite surprisingly, a massive increase in density of dendritic filopodia and spines in the affected neurons. This morphological change can be prevented in cultures ex-posed to calcium-free medium, to Orai1 antagonist 2APB, or to cells transfected with domi-nant-negative Orai1 plasmid. It is suggested that CCCP activates mitochondria through influx of calcium, to cause a rapid growth of dendritic processes