BASP1 Couples Ca2+ Signaling and Actin Polymerization to Mitochondrial Fission Essential for Neurite Outgrowth

Actin-mediated mitochondrial fission is essential for cellular homeostasis, yet the mechanisms by which actin is recruited to mitochondria and how it couples the outer and inner mitochondrial membranes (IMM) remain poorly understood. Using a phosphoproteomic screen in a rat model of -synucleinopathy, we identified BASP1 as a calcineurin-dependent substrate that is constitutively dephosphorylated under pathological Ca2+ elevations and phosphorylated under neuroprotective calcineurin inhibition. Immunoprecipitation and mass spectrometry of phosphomutant BASP1 expressed in neurons revealed that dephosphorylation promotes interactions with actin and IMM proteins. Dephosphorylated BASP1 recruits actin to mitochondria, while subsequent phosphorylation enables actin-mediated mitochondrial fission and neurite elongation. Constitutive dephosphorylation, as it occurs in -synucleinopathy, impairs mitochondrial fission, inhibits neurite growth and promotes -synuclein aggregation. Our findings position BASP1 as a Ca2+-CaN-regulated hub that coordinates actin remodeling and couples mitochondrial membranes to drive fission, revealing a mechanistic axis linking mitochondrial dysfunction to neuronal morphogenesis and -synuclein pathobiology.