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Updated: Aug 10, 2026

Characterization of MLKL-mediated Plasma Membrane Rupture in Necroptosis
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Bcl-xL mediates RIPK3-dependent necrosis in M. tuberculosis-infected macrophages

X Zhao1, N Khan2, H Gan1

  • 1Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

Mucosal Immunology
|April 13, 2017
PubMed

Insights

Necrosis of Mycobacterium tuberculosis (Mtb)-infected macrophages is crucial for tuberculosis pathogenesis. Blocking Receptor Interacting Protein Kinase 3 (RIPK3) and B-cell lymphoma-extra large (Bcl-xL) prevents Mtb spread.

Area of Science:

  • Immunology
  • Cell Biology
  • Microbiology

Background:

  • Virulent Mycobacterium tuberculosis (Mtb) infection induces host macrophage (Mϕ) necrosis, a key factor in tuberculosis pathogenesis.
  • Understanding the molecular mechanisms driving Mtb-induced necrosis is critical for developing novel therapeutic strategies.

Purpose of the Study:

  • To elucidate the molecular pathways governing Mtb-induced Mϕ necrosis.
  • To investigate the roles of Receptor Interacting Protein Kinase 3 (RIPK3) and B-cell lymphoma-extra large (Bcl-xL) in Mtb pathogenesis.

Main Methods:

  • Utilized Mtb-infected Mϕ models in vitro and in vivo.
  • Investigated the translocation of cytosolic RIPK3 to mitochondria.
  • Assessed the impact of RIPK3 deficiency on bacterial control.
  • Analyzed mitochondrial events including hexokinase II stabilization and cyclophilin D-dependent permeability transition.

Main Results:

  • Mtb-induced Mϕ necrosis is dependent on cytosolic RIPK3 and mitochondrial Bcl-xL.
  • RIPK3-deficient Mϕ exhibit enhanced control of Mtb growth.
  • RIPK3 translocates to mitochondria, promoting necrosis and inhibiting apoptosis by blocking caspase 8 activation via Bcl-xL.
  • Necrosis involves mitochondrial hexokinase II stabilization, cyclophilin D-dependent mitochondrial permeability transition, and increased reactive oxygen species.

Conclusions:

  • Mitochondria serve as a critical platform for Mtb-induced necrosis in Mϕ.
  • Targeting RIPK3 activation and mitochondrial pathways offers a potential therapeutic avenue for tuberculosis.

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