Mitochondria are not just the powerhouse of the cell. Known for their role in energy production and metabolism, they also play a significantly in the immune system1. While oxidative phosphorylation is the primary pathway of energy production in higher organisms, this process is oxygen-demanding and relatively slow under stressful conditions. Therefore, mitochondria can switch to glycolysis, a rapid energy-production method independent of oxygen supply2. External stressors, like pathogen-specific metabolites, can also alter mitochondrial metabolism to favour pathogen survival and replication1,3.
Notably, mitochondria can facilitate immune responses at the cellular level. They can transition from a catabolic, energy-producing phase to an anabolic phase to maximize the use of metabolites for both adenosine triphosphate (ATP) production (the cellular form of energy) and cellular homeostasis4. Additionally, mitochondria generate reactive oxygen species (ROS) that activate inflammatory pathways within the cell to bolster protection against intracellular pathogens. ROS also activates essential immune cell subsets such as macrophages and T cells to control and clear extracellular pathogens4. This article will explore the intricate interplay between mitochondrial metabolism and various bacterial and viral infections.
Mitochondria and bacterial infections: Legionnaire’s Disease
Legionnaire’s disease, a severe and potentially fatal bacterial pneumonia, is caused by Legionella pneumophila, an intracellular bacterium. Upon entry into human lung macrophages, L. pneumophila injects pathogenic proteins into the cell to initiate bacterial replication5,6. This interaction has piqued great interest in better understanding Legionella infections since macrophages activation are largely influenced by mitochondrial metabolic responses7,8. In 1983 L. pneumophila was observed to form Legionella-containing vacuoles (LCVs) upon entry into macrophages and later associate with the mitochondria9. Recent studies have shed further light on how LCVs can cause mitochondrial fragmentation, an indicator of cell death10. Mitochondrial fragmentation renders cells more susceptible to stressors and increases ROS production, where uncontrolled ROS output and oxidative stress can also induce cell death11,12.
Despite this, L. pneumophila did not induce other markers of cell death. Further analyses of macrophages’ metabolic rate after L. pneumophila infection revealed a shift from oxidative phosphorylation to glycolysis10, a less sustainable option for long-term cell survival and energy production13. One bacterial metabolite, which is injected into cells upon macrophage entry, Ceg3, may interfere with a component of the oxidative phosphorylation pathway, potentially impacting ATP output and subsequent cellular function14.
Metabolic alterations that may favor glycolysis over oxidative phosphorylation resemble the Warburg effect observed in cancer cells, which allows for uncontrolled and deleterious cell division2,10,13,14. Understanding the intricacies of this relationship between L. pneumophila infection and mitochondrial involvement provides valuable insights into the mechanisms of Legionnaire’s disease and potential avenues for therapeutic interventions.
Mitochondria and viral infections: long COVID
Long COVID, or post-acute COVID-19 syndrome, is a condition characterized by long-term symptoms appearing after the resolution of a SARS-CoV-2 infection and affects 10% of all infected individuals15. The severity of the initial infection is closely tied to the risk of developing long COVID and profoundly impacts the quality of life16,17. Metabolic perturbations, particularly involving iron deposition and mitochondrial association in the liver, are strongly linked to the severity of SARS-CoV-2 disease18,19. Elevated iron levels can lead to tissue damage, and disruptions in mitochondrial oxidative phosphorylation can also disrupt iron metabolism, leading to tissue inflammation in a positive feedback manner19,20.
Aside from external metabolites that serve as an indicator of COVID-19 illness severity, the mitochondrial DNA (mtDNA), a unique set of DNA within the mitochondria which governs metabolic function independently of the cell’s nuclear DNA, may serve as a biomarker for the organism’s ability to fight against infections and diseases21. High levels of circulating mtDNA in the blood are associated with inflammation and linked to the severity of the initial SARS-CoV-2 infection18,22. Tissue damage during SARS-CoV-2 infections, may increase oxidative stress, alter mtDNA, and decrease oxidative phosphorylation efficiency, thereby reducing metabolic capacity23. Additionally, viral infections can lead to the expulsion of damaged mtDNA from cells, suggesting that individuals with lower mitochondrial reserves may be more susceptible to long COVID24,25.
Host cells can also modulate metabolism to fight against SARS-CoV-2. For instance, manipulating iron metabolism and metabolite consumption via mitochondrial remodelling may be a form of starvation to slow viral replication26. Metabolites like succinate, found within oxidative phosphorylation pathways, also play important roles in inflammation, immunomodulation, and anti-viral activity27,28. During hypoxic conditions caused by lung infections, alterations in oxidative phosphorylation lead to succinate buildup, causing generation of excess ROS within the mitochondria11. This suggests the importance of mitochondrial health for viral resistance, but also its tolerance against oxidative stress and ability to consume high levels of ROS12,18.
Similar to L. pneumophila infections, SARS-CoV-2 viral proteins can inhibit components of oxidative phosphorylation, disrupt ATP output, enhance mitochondrial fragmentation, and induce cell death24. These mitochondrial perturbations suggest a shift towards glycolysis, indicating that SARS-CoV-2 infections may heighten the risk of cancer. Altogether, severe COVID-19 infections may be associated with lung injuries due to mitochondrial damage, but it remains elusive what proportion of these effects are caused by host versus viral effects24.
Conclusions
From Legionella bacterial infections to SARS-CoV-2 and post-acute COVID-19 syndrome, mitochondria play crucial roles in shaping disease outcomes. Pathogens can dynamically interact with mitochondria, potentially induce fragmentation and compromise cellular metabolism10,29. Understanding of how mitochondrial disease impacts immunity has led to hypotheses of treatments options, like transferring healthy stem cells to “donate” mitochondria to host cells garnering the virus and damaged mitochondria30. Continued research in the field of mitochondria is encouraged to foster the development of targeted therapeutic approaches.
References
1. Elesela, S. & Lukacs, N. W. Role of Mitochondria in Viral Infections. Life 11, 232 (2021).
2. Zheng, J. Energy metabolism of cancer: Glycolysis versus oxidative phosphorylation (review). Oncology Letters vol. 4 1151–1157 Preprint at https://doi.org/10.3892/ol.2012.928 (2012).
3. Eisner, V., Picard, M. & Hajnóczky, G. Mitochondrial dynamics in adaptive and maladaptive cellular stress responses. Nature Cell Biology vol. 20 755–765 Preprint at https://doi.org/10.1038/s41556-018-0133-0 (2018).
4. Angajala, A. et al. Diverse Roles of Mitochondria in Immune Responses: Novel Insights Into Immuno-Metabolism. Front Immunol 9, (2018).
5. Sol, A. et al. Legionella pneumophila translocated translation inhibitors are required for bacterial-induced host cell cycle arrest. Proc Natl Acad Sci U S A 116, 3221–3228 (2019).
6. Khweek, A. A. & Amer, A. Replication of Legionella pneumophila in human cells: Why are we susceptible? Front Microbiol 1, (2010).
7. Rosales, C. & Uribe-Querol, E. Phagocytosis: A Fundamental Process in Immunity. BioMed Research International vol. 2017 Preprint at https://doi.org/10.1155/2017/9042851 (2017).
8. O’Neill, L. A. J. & Pearce, E. J. Immunometabolism governs dendritic cell and macrophage function. Journal of Experimental Medicine vol. 213 15–23 Preprint at https://doi.org/10.1084/jem.20151570 (2016).
9. Horwitz, M. A. Formation of a novel phagosome by the Legionnaires’ disease bacterium (Legionella pneumophila) in human monocytes. J Exp Med 158, 1319–1331 (1983).
10. Escoll, P. et al. Legionella pneumophila Modulates Mitochondrial Dynamics to Trigger Metabolic Repurposing of Infected Macrophages. Cell Host Microbe 22, 302-316.e7 (2017).
11. Roca, F. J., Whitworth, L. J., Prag, H. A., Murphy, M. P. & Ramakrishnan, L. Tumor necrosis factor induces pathogenic mitochondrial ROS in tuberculosis through reverse electron transport. Science (1979) 376, (2022).
12. Munro, D., Baldy, C., Pamenter, M. E. & Treberg, J. R. The exceptional longevity of the naked mole‐rat may be explained by mitochondrial antioxidant defenses. Aging Cell 18, e12916 (2019).
13. García-Rodríguez, F. J., Buchrieser, C. & Escoll, P. Legionella and mitochondria, an intriguing relationship. in International Review of Cell and Molecular Biology vol. 374 37–81 (Elsevier Inc., 2023).
14. Fu, J. et al. Legionella pneumophila modulates host energy metabolism by ADP-ribosylation of ADP/ATP translocases. Elife 11, (2022).
15. Ballering, A. V, van Zon, S. K. R., Olde Hartman, T. C., Rosmalen, J. G. M. & Lifelines Corona Research Initiative. Persistence of somatic symptoms after COVID-19 in the Netherlands: an observational cohort study. Lancet 400, 452–461 (2022).
16. Davis, H. E., McCorkell, L., Vogel, J. M. & Topol, E. J. Long COVID: major findings, mechanisms and recommendations. Nature Reviews Microbiology vol. 21 133–146 Preprint at https://doi.org/10.1038/s41579-022-00846-2 (2023).
17. O’ Mahony, L. et al. Impact of Long COVID on health and quality of life. HRB Open Res 5, 31 (2022).
18. Nunn, A. V. W., Guy, G. W., Brysch, W. & Bell, J. D. Understanding Long COVID; Mitochondrial Health and Adaptation—Old Pathways, New Problems. Biomedicines vol. 10 Preprint at https://doi.org/10.3390/biomedicines10123113 (2022).
19. Del Nonno, F. et al. Hepatic failure in covid-19: Is iron overload the dangerous trigger? Cells 10, (2021).
20. Captur, G. et al. Plasma proteomic signature predicts who will get persistent symptoms following SARS-CoV-2 infection. EBioMedicine 85, 104293 (2022).
21. Atig, R. K.-B., Hsouna, S., Beraud-Colomb, E. & Abdelhak, S. [Mitochondrial DNA: properties and applications]. Arch Inst Pasteur Tunis 86, 3–14 (2009).
22. Scozzi, D. et al. C L I N I C A L M E D I C I N E Circulating mitochondrial DNA is an early indicator of severe illness and mortality from COVID-19. (2021) doi:10.1172/jci.
23. Stenberg, S. et al. Genetically controlled mtDNA deletions prevent ROS damage by arresting oxidative phosphorylation. Elife 11, (2022).
24. Archer, S. L. et al. SARS-CoV-2 mitochondriopathy in COVID-19 pneumonia exacerbates hypoxemia. Redox Biol 58, (2022).
25. Mehra, C. & Pernas, L. Move it to lose it: Mitocytosis expels damaged mitochondria. Dev Cell 56, 2014–2015 (2021).
26. Pernas, L. Cellular metabolism in the defense against microbes. J Cell Sci 134, (2021).
27. Sánchez-García, F. J., Pérez-Hernández, C. A., Rodríguez-Murillo, M. & Moreno-Altamirano, M. M. B. The Role of Tricarboxylic Acid Cycle Metabolites in Viral Infections. Front Cell Infect Microbiol 11, (2021).
28. Guillon, A. et al. Host succinate inhibits influenza virus infection through succinylation and nuclear retention of the viral nucleoprotein. EMBO J 41, (2022).
29. Kim, E. S. et al. Mitochondrial dynamics regulate melanogenesis through proteasomal degradation of MITF via ROS-ERK activation. Pigment Cell Melanoma Res 27, 1051–1062 (2014).
30. Babajani, A., Hosseini-Monfared, P., Abbaspour, S., Jamshidi, E. & Niknejad, H. Targeted Mitochondrial Therapy With Over-Expressed MAVS Protein From Mesenchymal Stem Cells: A New Therapeutic Approach for COVID-19. Front Cell Dev Biol 9, (2021).
Jinny Tsang
