Volume 84, October 2023, 102366Author links open overlay panel, ,

In addition to housing the major energy-producing pathways in cells, mitochondria are active players in innate immune responses. One critical way mitochondria fulfill this role is by releasing damage-associated molecular patterns (mtDAMPs) that are recognized by innate sensors to activate pathways including, but not limited to, cytokine expression, selective autophagy, and cell death. Mitochondrial reactive oxygen species (mtROS) is a multifunctional mtDAMP linked to pro- and antimicrobial immune outcomes. Formed as a by-product of energy generation, mtROS links mitochondrial metabolism with downstream innate immune responses. As a result, altered cellular metabolism can change mtROS levels and impact downstream antimicrobial responses in a variety of ways. MtROS has emerged as a particularly important mediator of pathogenesis during infection with Mycobacterium tuberculosis (Mtb), an intracellular bacterial pathogen that continues to pose a significant threat to global public health. Here, we will summarize how Mtb modulates mtROS levels in infected macrophages and how mtROS dictates Mtb infection outcomes by controlling inflammation, lipid peroxidation, and cell death. We propose that mtROS may serve as a biomarker to predict tuberculosis patient outcomes and/or a target for host-directed therapeutics.

Section snippetsMitochondrial reactive oxygen species in cellular metabolism and homeostasis

Generation of mitochondrial reactive oxygen species (mtROS) is a natural consequence of the electron transport chain (ETC). The ETC operates as a series of complexes spanning the inner mitochondrial membrane that shuttles high-energy electrons sourced from nicotinamide adenine dinucleotide (NADH) or flavin adenine dinucleotide (FADH2), produced by glycolysis or the Krebs cycle, to generate an electrochemical proton gradient. As this gradient is generated, some electrons escape the normal ETC.

Mitochondrial reactive oxygen species in infection and immunity

Generation of cellular ROS is traditionally thought of as an antimicrobial strategy. Work from the O’Riordan lab and others shows that endoplasmic reticulum stress stimulates mitochondria via IRE1α to produce vesicles containing SOD2. SOD2-containing vesicles are delivered to bacteria-containing phagosomes where SOD2 catalyzes peroxide production, which can control bacterial burdens in the case of methicillin-resistant Staphylococcus aureus infections [1]. In Mycobacterium avium infection,

Mitochondrial reactive oxygen species in cell death

One way that mtROS promotes mycobacterial pathogenesis is by acting as a DAMP to activate cell death pathways that help Mtb spread to neighboring cells and/or create a probacterial inflammatory milieu. Early studies linked mtROS to a form of inflammatory cell death known as pyroptosis [51]. During pyroptosis, assembly of the inflammasome activates caspase-1, which cleaves IL-1β and gasdermin D (GSDMD), the latter of which forms pores in the plasma membrane and promotes membrane rupture with the

Concluding remarks

As studies continue to link mitochondrial dysfunction and oxidative stress with poor tuberculosis disease outcomes, the mycobacterium field is experiencing a paradigm shift regarding the role of antimicrobial mediators such as mtROS in Mtb pathogenesis. Outstanding questions of key importance include how mtROS impacts the biology of both host and bacterial lipids. We know that fatty acids, rather than carbohydrates, are the major energy source for Mtb inside macrophages 12, 24. Are these lipids

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

Our apologies to the authors of reports that could not be highlighted due to space limitations. This work was supported by National Institute of Allergy and Infectious Diseases NIH/NIAID, USA R01AI155621 to ROW and KP.

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