TNF Induces Pathogenic Programmed Macrophage Necrosis in Tuberculosis Through a Mitochondrial-Lysosomal-Endoplasmic Reticulum Circuit

Cell. 2019 Sep 5;178(6):1344-1361.e11. doi: 10.1016/j.cell.2019.08.004. Epub 2019 Aug 29.

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.

Keywords: BAX; Calcium; ER; ROS; TNF-mediated necrosis; calcium channel blockers; macrophage; mitochondrion; ryanodine receptors; tuberculosis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Calcium / metabolism
  • Endoplasmic Reticulum / microbiology
  • Humans
  • Lysosomes / microbiology
  • Macrophages / microbiology*
  • Macrophages / pathology*
  • Membrane Potential, Mitochondrial
  • Mitochondria / metabolism*
  • Mycobacterium Infections, Nontuberculous / metabolism*
  • Mycobacterium Infections, Nontuberculous / pathology
  • Mycobacterium marinum
  • Mycobacterium tuberculosis
  • Necrosis
  • Reactive Oxygen Species / metabolism
  • THP-1 Cells
  • Tuberculosis / immunology*
  • Tuberculosis / pathology*
  • Tumor Necrosis Factor-alpha / metabolism*
  • Zebrafish

Substances

  • Reactive Oxygen Species
  • Tumor Necrosis Factor-alpha
  • Calcium