Mycobacterium tuberculosis virulence correlates with mitochondrial cytochrome c release in infected macrophages

Abstract

Mitochondria are at the centre of molecular events involved in energy production, cell survival and apoptosis. Mitochondrial membrane potential (Deltapsim) is maintained by cellular catabolic reactions and the electron transport chain of which cytochrome c is a constituent, whereas the proton leak pathway, ATP synthesis and turnover consume it. Mitochondrial alterations such as a drop in Deltapsim, swelling and cytochrome c release have been observed in apoptosis. However, there is a paucity of information concerning mitochondrial function in the course of intracellular infections, a process that must certainly induce stress on the host cell. This work analyses the effect that two strains of mycobacteria of opposing virulence have on the mitochondria of murine macrophages in the early stages of infection. It was found that infection of J774 cells with both Mycobacterium tuberculosis H37Ra and M. tuberculosis H37Rv readily induced changes in Deltapsim as well as in mitochondrial morphology at the ultrastructural level. In addition, an increase in cytosolic ATP was found at 24 h post infection with both strains of M. tuberculosis. Interestingly, only M. tuberculosis H37Rv was able to induce cytochrome c release from mitochondria to the cytosol, thus suggesting the occurrence in M. tuberculosis H37Rv of a specific factor(s) capable of regulating cytochrome c translocation. The precise role of cytochrome c release in the context of a mycobacterial infection remains to be elucidated.