Related Experiment Video
Updated: Jan 20, 2026
Endoplasmic Reticulum : RER and SER
TNF Induces Pathogenic Programmed Macrophage Necrosis in Tuberculosis through a Mitochondrial-Lysosomal-Endoplasmic
Francisco J Roca1, Laura J Whitworth1, Sarah Redmond2
1Molecular Immunity Unit, Department of Medicine, University of Cambridge, MRC Laboratory of Molecular Biology, Cambridge CB2 OQH, UK.
Abstract:
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.
Insights
Necrosis of infected macrophages in tuberculosis releases mycobacteria extracellularly. Targeting calcium channels and ryanodine receptors can block this programmed cell death in macrophages.
Area of Science:
- Cell Biology
- Immunology
- Microbiology
Background:
- Macrophage necrosis is crucial in tuberculosis pathogenesis, enabling mycobacteria spread.
- Tumor necrosis factor (TNF) induces macrophage necrosis via mitochondrial reactive oxygen species (ROS) and cyclophilin D.
Purpose of the Study:
- To elucidate the inter-organellar signaling pathway triggering programmed necrosis in mycobacterium-infected macrophages.
- To identify druggable targets for preventing macrophage necrosis.
Main Methods:
- Utilized zebrafish infection models with Mycobacterium marinum and Mycobacterium tuberculosis.
- Investigated the roles of mitochondrial ROS, lysosomal ceramide, BAX, and calcium signaling.
- Examined the involvement of ryanodine receptors and L-type calcium channels.
Main Results:
- Macrophage necrosis is an inter-organellar circuit, not solely mitochondrion-intrinsic.
- Mitochondrial ROS induce lysosomal ceramide, activating cytosolic BAX.
- BAX facilitates endoplasmic reticulum calcium release into mitochondria, causing overload and necrosis.
Conclusions:
- Identified a novel pathway: mitochondrial ROS -> lysosomal ceramide -> BAX -> ER calcium release -> mitochondrial calcium overload -> necrosis.
- Ryanodine receptors and L-type calcium channels are key regulators and potential therapeutic targets.
- Blocking these targets can prevent necrosis in infected zebrafish and human macrophages.
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