Mycobacterium tuberculosis modulates mitochondrial function in human macrophages

Mitochondrial dynamics and metabolism in immune cells are closely associated. However, if these interactions play a role in the human macrophage response to Mycobacterium tuberculosis (Mtb) remains largely unknown.We used human induced-pluripotent stem cell derived macrophages (iPSDM) together with high-content live-cell imaging, extracellular flux analysis and unbiased metabolomics to investigate mitochondrial dynamics, Mtb intracellular replication and mitochondrial metabolism.Mitochondrial tracking at the single-cell level revealed extensive mitochondrial morphology heterogeneity. Surprisingly, Mtb did not induce significant changes in the mitochondrial area, length or width during the first 48h of infection. We did not find a correlation between Mtb intracellular replication and changes in mitochondrial morphological parameters. However, Mtb induced a decrease in the mitochondrial membrane potential and protein turnover rate, as visualised by MitoTracker Red and the ratiometric reporter MitoTimer, respectively.The metabolic profile of infected macrophages showed an increase in oxygen consumption and extracellular acidification rate after 48h of infection. These changes were associated with decreased mitochondrial protein and transcripts levels. The inhibition of glycolysis with 2-Deoxy-d-glucose promoted Mtb replication, whereas oxamate (lactate dehydrogenase inhibitor) impaired Mtb intracellular replication.Collectively, our results show that macrophage metabolic reprogr...
Source: European Respiratory Journal - Category: Respiratory Medicine Authors: Tags: Tuberculosis Source Type: research