-induced ER-Mitochondrial calcium dynamics promotes calpain/caspase-12/caspase-9 mediated apoptosis in fish macrophages.

is a natural fish pathogen. It induces apoptosis in headkidney macrophages (HKM) of catfish, sp though the mechanism remains largely unknown. We observed triggers calcium (Ca) insult in the sub-cellular compartments which elicits pro-apototic ER-stress factor CHOP. Alleviating ER-stress inhibited CHOP and attenuated HKM apoptosis implicating ER-stress in the pathogenesis of . ER-stress promoted calpain activation and silencing the protease inhibited caspase-12 activation. The study documents the primal role of calpain/caspase-12 axis on caspase-9 activation in -pathogenesis. Mobilization of Ca from ER to mitochondria led to increased mitochondrial Ca (Ca) load, mitochondrial permeability transition (MPT) pore opening, altered mitochondrial membrane potential (ΔΨm) and cytochrome release eventually activating the caspase-9/-3 cascade. Ultra-structural studies revealed close apposition of ER and mitochondria and pre-treatment with (Ca)-uniporter (MUP) blocker ruthenium red, reduced Ca overload suggesting (Ca) fluxes are MUP-driven and the ER-mitochondria tethering orchestrates the process. This is the first report implicating role of sub-cellular Ca in the pathogenesis of . We summarize, the dynamics of Ca in sub-cellular compartments incites ER-stress and mitochondrial dysfunction, leading to activation of pro-apoptotic calpain/caspase-12/caspase-9 axis in -infected HKM.