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Necrosis of infected macrophages constitutes a critical pathogenetic event in tuberculosis by releasing mycobacteria into the growth-permissive extracellular environment. In zebrafish infected with Mycobacterium marinum or Mycobacterium tuberculosis , excess tumor necrosis factor triggers programmed necrosis of infected macrophages through the production of mitochondrial reactive oxygen species (ROS) and the participation of cyclophilin D, a component of the mitochondrial permeability transition pore. Here, we show that this necrosis pathway is not mitochondrion-intrinsic but results from an inter-organellar circuit initiating and culminating in the mitochondrion. Mitochondrial ROS induce production of lysosomal ceramide that ultimately activates the cytosolic protein BAX. BAX promotes calcium flow from the endoplasmic reticulum into the mitochondrion through ryanodine receptors, and the resultant mitochondrial calcium overload triggers cyclophilin-D-mediated necrosis. We identify ryanodine receptors and plasma membrane L-type calcium channels as druggable targets to intercept mitochondrial calcium overload and necrosis of mycobacterium-infected zebrafish and human macrophages. • TNF induces mitochondrial ROS to cause necrosis of mycobacterium-infected macrophages • Mitochondrial ROS activate lysosomal enzymes that lead to BAX activation • BAX activates ER ryanodine receptors to cause Ca2+ flow into the mitochondrion • Drugs preventing mitochondrial Ca2+ overload prevent pathogenic macrophage necrosis in TB During TB infection, the necrosis of infected macrophages involves an inter organelle signaling relay involving druggable targets such as ryanodine receptors and plasma membrane L-type Ca2+ channels. [ABSTRACT FROM AUTHOR]