DOI: 10.1101/511436Jan 3, 2019Paper

Tumor Necrosis Factor induces pathogenic programmed macrophage necrosis in tuberculosis through a mitochondrial-lysosomal-endoplasmic reticulum circuit

BioRxiv : the Preprint Server for Biology
Francisco J RocaLalita Ramakrishnan

Abstract

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.

Related Concepts

Calcium
Plasma Membrane
Ceramides
Endoplasmic Reticulum
Environment
Macrophage Activation
Macrophage
Mitochondria
Genus Mycobacterium
Mycobacterium tuberculosis

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