Author response: Mycobacterium tuberculosis induces decelerated bioenergetic metabolism in human macrophages

Cumming, Bridgette M.; Addicott, Kelvin W; Adamson, John; Steyn, Adrie

doi:10.7554/elife.39169.018

Cited by 13 publications

(22 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In contrast, the ATP/ADP ratios reported by Jamwal et al under similar conditions reveal a reverse trend, wherein the virulent Mtb showed a significant increase in ATP/ADP ratio as compared to avirulent Mtb H37Ra (Jamwal et al, 2013). LC-MS/MS, in conjunction with 13 C-tracing, showed reduced enrichment of TCA metabolites in the Mtb-infected hMDMs suggesting a decelerated bioenergetic metabolism (Cumming et al, 2018). While this study established robust quantifiable bioenergetic parameters, some of the observations also challenged the general dogma in the field.…”

Section: Changes In Mitochondrial Bioenergeticsmentioning

confidence: 66%

“…With the availability of real-time live-cell metabolic assay platforms for measuring oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) for examining mitochondrial respiration and glycolysis, respectively, mitochondrial bioenergetics have been investigated in detail. Perturbation in bioenergetics of mitochondria is largely a measure of some direct and derived parameters briefly discussed below and elaborated in the reference (Mills et al, 2016;Cumming et al, 2018). The assays rely on the usage of specific inhibitors such as oligomycin (ATP synthase inhibitor), rotenone (complex I inhibitor), and antimycin A (complex III inhibitor) and uncouplers like carbonyl cyanide-4-(trifluoromethoxy) phenylhydrazone (FCCP) that uncouples ATP synthesis from electron transport.…”

Section: Changes In Mitochondrial Bioenergeticsmentioning

confidence: 99%

“…Some of the basic parameters that have been compared between uninfected/unstimulated vs. infected/stimulated macrophages include non-mitochondrial respiration (OCR after inhibiting complex I and III), ATP-linked respiration (OCR after inhibiting ATP synthase), proton leak (ATP-linked OCR minus NMR); maximal respiration (OCR after uncoupling ATP synthesis from ETC) and spare respiratory capacity (the difference between maximal respiration and basal respiration). The studies applied these well-established protocols to measure the perturbations in host mitochondrial bioenergetics systematically suggesting bioenergetic links to macrophage pro-inflammatory response and mycobacterial infections (Mills et al, 2016;Cumming et al, 2018). Glycolytic parameters were measured as a function of ECAR with nonglycolytic acidification as the measurement of ECAR before adding glucose, and maximal glycolytic capacity (ECAR after inhibiting ATP synthase minus non-glycolytic acidification).…”

Section: Changes In Mitochondrial Bioenergeticsmentioning

confidence: 99%

“…They used two cell types (PMA differentiated THP-1 and hMDMs) and three types of treatments [with live virulent Mtb, the non-virulent vaccine strain, M. bovis BCG (BCG), and dead-Mtb preparation]. These observations showed that treated macrophages have disparate respiratory differences, which depended on cell type, the burden of infection, and pathogenicity of mycobacteria (Cumming et al, 2018). Like others, they also observed that Mtb infection depressed the rate of OXPHOS in macrophages.…”

Section: Changes In Mitochondrial Bioenergeticsmentioning

confidence: 99%

“…A more in-depth investigation using three substrates, glucose, glutamine and fatty acids, showed that Mtb infected hMDMs, use dominantly exogenous fatty acids rather than endogenous fatty acids under stress. hMDMs infected with M. bovis-BCG, the attenuated strain, utilizes both exogenous and endogenous sources of fatty acids, but unlike virulent Mtb strain, predominantly used endogenous fatty acid oxidation to meet energy requirement during stress (Cumming et al, 2018). These observations helped to dissect the finer steps of lipid utilization by Mtb during infection.…”

Section: Lipid Droplet and Foamy Macrophagesmentioning

confidence: 99%

See 4 more Smart Citations

Mycobacterial Control of Host Mitochondria: Bioenergetic and Metabolic Changes Shaping Cell Fate and Infection Outcome

Mohareer

Medikonda

Vadankula

et al. 2020

Front. Cell. Infect. Microbiol.

View full text Add to dashboard Cite

Mitochondria, are undoubtedly critical organelle of a eukaryotic cell, which provide energy and offer a platform for most of the cellular signaling pathways that decide cell fate. The role of mitochondria in immune-metabolism is now emerging as a crucial process governing several pathological states, including infection, cancer, and diabetes. Mitochondria have therefore been a vulnerable target for several bacterial and viral pathogens to control host machinery for their survival, replication, and dissemination. Mycobacterium tuberculosis, a highly successful human pathogen, persists inside alveolar macrophages at the primary infection site, applying several strategies to circumvent macrophage defenses, including control of host mitochondria. The infection perse and specific mycobacterial factors that enter the host mitochondrial milieu perturb mitochondrial dynamics and function by disturbing mitochondrial membrane potential, shifting bioenergetics parameters such as ATP and ROS, orienting the host cell fate and thereby infection outcome. In the present review, we attempt to integrate the available information and emerging dogmas to get a holistic view of Mycobacterium tuberculosis infection visa -vis mycobacterial factors that target host mitochondria and changes therein in terms of morphology, dynamics, proteomic, and bioenergetic alterations that lead to a differential cell fate and immune response determining the disease outcome. We also discuss critical host factors and processes that are overturned by Mycobacterium tuberculosis, such as cAMP-mediated signaling, redox homeostasis, and lipid droplet formation. Further, we also present alternate dogmas as well as the gaps and limitations in understanding some of the present research areas, which can be further explored by understanding some critical processes during Mycobacterium tuberculosis infection and the reasons thereof. Toward the end, we propose to have a set of guidelines for pursuing investigations to maintain uniformity in terms of early and late phase, MOI of infection, infection duration and incubation periods, the strain of mycobacteria, passage numbers, and so on, which all work as probable variables toward different readouts. Such a setup would, therefore, help in the smooth integration of information across laboratories toward a better understanding of the disease and possibilities of host-directed therapy.

show abstract

Section: Changes In Mitochondrial Bioenergeticsmentioning

confidence: 66%

Section: Changes In Mitochondrial Bioenergeticsmentioning

confidence: 99%

Section: Changes In Mitochondrial Bioenergeticsmentioning

confidence: 99%

Section: Changes In Mitochondrial Bioenergeticsmentioning

confidence: 99%

Section: Lipid Droplet and Foamy Macrophagesmentioning

confidence: 99%

See 3 more Smart Citations