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Critical Role of Mitochondrial Damage in Determining Outcome of Macrophage Infection with Mycobacterium tuberculosis¹

Lei Duan^2,*, Huixian Gan^2,*, David E. Golan and Heinz G. Remold^3,*

^* Division of Rheumatology and Immunology, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, and Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115

Human macrophages (M) 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, M 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 Ca²⁺ concentration ([Ca²⁺]_m) determine whether M undergo either apoptosis or necrosis. Therefore, we induced mechanism(s) leading to predominant apoptosis or necrosis by modulating [Ca²⁺]_m and examined their physiological consequences. Adding calcium ionophore A23187 to M inoculated with Mtb further increased calcium flux into the cells which is thought to lead to increased [Ca²⁺]_m, blocked necrosis, stabilized MPT, decreased mitochondrial cytochrome c release, lowered caspase activation, and accompanied effective antimycobacterial activity. In contrast, M 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 M, 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.

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