Last week’s journal club paper was presented by Lavanya Mane, a member of Prof Rob Heyderman’s and Prof Robert Wilkinson’s groups. She presented the paper “Lactate oxidation facilitates growth of Mycobacterium tuberculosis in human macrophages”. Below, she provides her commentary and opinion on the paper.
The nutritional flexibility of M. tuberculosis (Mtb) along with its ability to co-metabolise multiple substrates is well-known, and lends the pathogen immense adaptability. In response to an infection, immune cells (including macrophages) switch from oxidative phosphorylation to aerobic glycolysis in order to meet increased energy requirements, generating lactate in the process - a process often referred to as the Warburg effect.
Researchers from Hannover Medical School demonstrate for the first time that Mtb can utilise L-lactate as a sole carbon source for growth in vitro, and that this is contingent on the presence of a mycobacterial quinone-dependent lactate dehydrogenase, LldD2. Carbon-13 labelling reveals lactate is metabolised predominantly via gluconeogenesis to generate biomass. As gluconeogenic enzymes have previously been shown to be crucial for intracellular survival of M. tuberculosis, this highlights the benefit of lactate utilisation.
Removal of LldD2 in the knockout strain ∆lldd2 renders the organisms unable to proliferate in human monocyte-derived macrophages. The authors interpret this to mean lactate oxidation is essential for intracellular growth of Mtb in macrophages, although the study itself shows that LldD2 has a role in metabolising other compounds. In addition, the authors demonstrate that excessive lactate considerably slows the growth of Mtb in culture, speculating this may be related to lactate production correlating with increases in oxidative stress.
Therefore, this paper seems to demonstrate that through expression of the lactate dehydrogenase LldD2 within a macrophage that has been activated and undergoing a Warburg switch in its metabolism, Mtb can not only remove accumulated lactate to prevent ROS build-up but also consume lactate as a source of energy to facilitate its survival and growth. Looks like Mtb is once again making the most of its environment to its own advantage and it also renders LldD2 an attractive drug target for researchers with the skills to make things like that!