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TNF induces pathogenic programmed macrophage necrosis in Tuberculosis through a mitochondrial- lysosomal-endoplasmic reticulum circuit

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dc.contributor.authorRoca Soler, Francisco José
dc.contributor.authorWhitworth, Laura J.
dc.contributor.authorRedmond, Sarah
dc.contributor.authorJones, Ana A.
dc.contributor.authorRamakrishnan, Lalita
dc.contributor.departmentBioquímica y Biología Molecular B e Inmunología
dc.date.accessioned2026-02-25T16:03:08Z
dc.date.available2026-02-25T16:03:08Z
dc.date.copyright© 2019 The Author(s)
dc.date.issued2019-08-29
dc.description.abstractNecrosis 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.
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dc.identifier.citationCell 178, 1344–1361, September 5, 2019
dc.identifier.eissn1097-4172
dc.identifier.issn0092-8674
dc.identifier.urihttp://hdl.handle.net/10201/213541
dc.languageeng
dc.publisherCell Press
dc.relationThis work was supported by an NIH MERIT award (R37AI054503) and a Wellcome Trust Principal Research Fellowship to L.R. S.R. was a Mary Gates Undergraduate Research Scholar for part of the study.
dc.relation.publisherversionhttps://www.sciencedirect.com/science/article/pii/S009286741930892X
dc.rightsAttribution 4.0 International
dc.rights.accessRightsinfo:eu-repo/semantics/openAccess
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectTNF mediated necrosis
dc.subjectMacrophage
dc.subjectTuberculosis
dc.subjectMitochondrion
dc.subjectROS
dc.subjectCalcium
dc.subjectBAX
dc.subjectER
dc.subjectRyanodine receptors
dc.subjectCalcium channel blockers
dc.subject.odsObjetivo 3: Salud
dc.titleTNF induces pathogenic programmed macrophage necrosis in Tuberculosis through a mitochondrial- lysosomal-endoplasmic reticulum circuit
dc.typeinfo:eu-repo/semantics/article
dc.type.versioninfo:eu-repo/semantics/publishedVersion
dspace.entity.typePublicationes
relation.isAuthorOfPublication7f46a88a-1ff4-4f80-948e-7d636b80e75d
relation.isAuthorOfPublication.latestForDiscovery7f46a88a-1ff4-4f80-948e-7d636b80e75d
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