Abstract
SUMMARY
Necrosis of infected macrophages constitutes a critical pathogenetic event
in tuberculosis releasing mycobacteria into the extracellular environment where
they can grow unrestricted. In zebrafish infected with
Mycobacterium marinum, a close relative of
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
rather results from an interorganellar circuit initiating and culminating in the
mitochondrion. Mitochondrial ROS induce production of lysosomal ceramide which
ultimately activates the cytosolic protein BAX. BAX promotes calcium flow from
the endoplasmic reticulum into the mitochondrion through ryanodine receptors.
The resultant mitochondrial calcium overload triggers cyclophilin D-mediated
necrosis. We identify ryanodine receptors and plasma membrane L-Type calcium
channels as specific druggable targets to intercept mitochondrial calcium
overload so as to inhibit macrophage necrosis.
Publisher
Cold Spring Harbor Laboratory