Hypoxia and classical activation limits Mycobacterium tuberculosis survival by Akt-dependent glycolytic shift in macrophages

• Published in: Cell death discovery 2016-05, Vol.2 (1), p.16022-16022, Article 16022
• Main Authors: Matta, S K, Kumar, D
• Format: Article
• Language: English
• Subjects: 631/250/2499; 631/80/82/23; Apoptosis; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Cycle Analysis; Life Sciences; Stem Cells
• ISSN: 2058-7716; 2058-7716
• DOI: 10.1038/cddiscovery.2016.22

Cellular reactive oxygen species (ROS) is a major antibacterial defense mechanism used by macrophages upon activation. Exposure of Mycobacterium tuberculosis ( Mtb )-infected macrophages to hypoxia is known to compromise the survival of the pathogen. Here we report that the hypoxia-induced control of intracellular Mtb load in RAW 264.7 macrophages was mediated by regulating the cellular ROS levels. We show that similar to classical activation, hypoxia incubation of macrophages resulted in decreased mitochondrial outer membrane potential (MOMP) and a concomitant increase in the cellular ROS levels. Mitochondrial depolarization and consequently higher ROS could be blocked by knocking down Akt using siRNAs, which acted by inhibiting the switch to glycolytic mode of metabolism, an essential adaptive response upon classical activation or hypoxic incubation of macrophages. Moreover, in the classically activated macrophages or in the macrophages under hypoxia incubation, supplementation with additional glucose had similar effects as Akt knockdown. Interestingly, in both the cases, the reversal of phenotype was linked with the ability of the mitochondrial F 0 –F 1 ATP synthase activity to maintain the MOMP in the absence of oxidative phosphorylation. Both Akt knockdown and glucose supplementation were also able to rescue Mtb survival in these macrophages upon classical activation or hypoxia incubation. These results provide a framework for better understanding of how the interplay between oxygen supply, which is limiting in the human tubercular granulomas, and nutrient availability could together direct the outcome of infections in vivo .