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

Abstract

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.

The Warburg Effect Occurs Rapidly in Stimulated Human Adult but Not Umbilical Cord Blood Derived Macrophages

“…Macrophage effector function is vital for Mtb control (42). Neonates are 5-10 fold more likely to develop infection (43,44) following exposure and alveolar macrophages from newborns are unable to control Mtb (45).…”

Mycobacterium tuberculosis RipA Dampens TLR4-Mediated Host Protective Response Using a Multi-Pronged Approach Involving Autophagy, Apoptosis, Metabolic Repurposing, and Immune Modulation

“…The classical foamy phenotype of infected macrophages is due to rewiring of the glycolytic pathway toward ketone body and lipid synthesis. Infected macrophages switch from pyruvate oxidation to the reduction of pyruvate into lactate that serves as an additional carbon substrate for M. tb ( 74 – 76 ). Although, yet to be validated, these effects point to TLR4-mediated HIF1-α activation possibly lead to the inhibition of oxidative phosphorylation and the activation of glycolysis to promote metabolic reprogramming.…”

An Indispensable Role for the MavE Effector of Legionella pneumophila in Lysosomal Evasion

“…These pathogenic mechanisms involve the injection or secretion of effectors into the host by various type I to IX translocation systems (59)(60)(61)(62) and are present in extracellular pathogens, such as Bordetella (63) as well. These effectors modulate various cellular processes as well as host metabolism to render the host cell suitable as a proliferative nutrient-rich niche (55,(64)(65)(66)(67)(68)(69)(70). Cytosolic pathogens, such as Rickettsia, have evolved to evade the host cytosolic antimicrobial processes (71,72).…”

“…Cytosolic pathogens, such as Rickettsia, have evolved to evade the host cytosolic antimicrobial processes (71,72). Modulation of host metabolism is a general common theme among intracellular pathogens, leading to a suitable nutritional niche for pathogen proliferation, and that has been well characterized for Mycobacterium (52,65,66,(73)(74)(75). For intravacuolar pathogens, the crux of these host processes is evasion of the endosomal-lysosomal degradation pathway by most intravacuolar pathogens, such as Mycobacterium, Chlamydia, and Salmonella (1, 2).…”