title: Critical role of mitochondrial damage in determining outcome of macrophage infection with Mycobacterium tuberculosis.
abstract: Human macrophages (Mphi) respond to Mycobacterium tuberculosis (Mtb) infection by undergoing apoptosis, a cornerstone of effective antimycobacterial host defense. Virulent mycobacteria override this reaction by inducing necrosis leading to uncontrolled Mtb replication. Accordingly, Mphi death induced by inoculation with Mtb had the characteristics of apoptosis and necrosis and correlated with moderate increase of mitochondrial permeability transition (MPT), mitochondrial cytochrome c release, and caspase-9 and -3 activation. We hypothesized that changes in intramitochondrial Ca(2+) concentration ([Ca(2+)](m)) determine whether Mphi undergo either apoptosis or necrosis. Therefore, we induced mechanism(s) leading to predominant apoptosis or necrosis by modulating [Ca(2+)](m) and examined their physiological consequences. Adding calcium ionophore A23187 to Mphi inoculated with Mtb further increased calcium flux into the cells which is thought to lead to increased [Ca(2+)](m), blocked necrosis, stabilized MPT, decreased mitochondrial cytochrome c release, lowered caspase activation, and accompanied effective antimycobacterial activity. In contrast, Mphi infected with Mtb in presence of the mitochondrial calcium uniporter inhibitor ruthenium red showed increased mitochondrial swelling and cytochrome c release and decreased MPT and antimycobacterial activity. Thus, in Mtb-infected Mphi, high levels of mitochondrial membrane integrity, low levels of caspase activation, and diminished mitochondrial cytochrome c release are hallmarks of apoptosis and effective antimycobacterial activity. In contrast, breakdown of mitochondrial membrane integrity and increased caspase activation are characteristic of necrosis and uncontrolled Mtb replication.
authors.affiliation: Division of Rheumatology and Immunology, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Duan
authors.forename: Huixian
authors.initials: H
authors.lastname: Gan
authors.forename: David E
authors.initials: DE
authors.lastname: Golan
authors.forename: Heinz G
authors.initials: HG
authors.lastname: Remold
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D001770:Blood Bactericidal Activity / Q000187:drug effects; D000001:Calcimycin / Q000494:pharmacology; D015220:Calcium Channels; D002135:Calcium-Binding Proteins / Q000037:antagonists & inhibitors; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D003574:Cytochrome c Group / Q000037:antagonists & inhibitors / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007425:Intracellular Membranes / Q000187:drug effects / Q000382:microbiology / Q000648:ultrastructure; D007476:Ionophores / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology / Q000382:microbiology* / Q000648:ultrastructure; D008564:Membrane Potentials / Q000187:drug effects / Q000276:immunology; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism / Q000382:microbiology* / Q000648:ultrastructure; D008933:Mitochondrial Swelling / Q000187:drug effects / Q000276:immunology*; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000254:growth & development / Q000276:immunology*; D009336:Necrosis; D010539:Permeability / Q000187:drug effects; D012430:Ruthenium Red / Q000494:pharmacology
chemical_list: D015220:Calcium Channels; D002135:Calcium-Binding Proteins; D061945:Caspase Inhibitors; D003574:Cytochrome c Group; D007476:Ionophores; C034703:mitochondrial calcium uniporter; D012430:Ruthenium Red; D000001:Calcimycin; D020169:Caspases