How Lyme Damages Your Mitochondria and Drives Chronic Fatigue
When individuals navigate the complex realities of tick- and vector-borne illnesses, the word fatigue doesn’t begin to capture the full extent of the exhaustion experienced. It goes beyond the typical recovery that comes with a good night’s sleep or taking it easy for a few days. It is a profound, system-wide energy deficit.
Borrelia burgdorferi, the bacterium that causes Lyme disease, disrupts mitochondrial function, which serves as both an energy producer and a sentinel essential to all biological processes. It is important to remember that the mitochondria produce more than 90% of the energy needed for the body’s biological processes.
Research indicates the body is affected by several types of disruption, rather than a single mechanism. Its reach is pervasive throughout the system in the following ways:
- Downregulates key metabolic enzymes ACSL1 and ACSS2 involved in fatty acid metabolism, driving the body toward glycolysis instead of oxidative phosphorylation, increasing the inflammatory response (Barriales et al., 2021).
- Disrupts ROS (reactive oxygen species) and reduction-oxidation (redox) balance (Kerstholt et al., 2022; Peacock et al., 2015).
- Releases bacterial extracellular vesicles (BEVs) that perpetuate mitochondrial damage and inflammation after the initial infection, leading to the debilitating fatigue and neuroinflammation associated with long-term Lyme disease (Nguyen et al., 2025).
To understand why and how Lyme disease depletes vitality at such a foundational level, it is key to look beyond the surface symptoms associated with the diagnosis and examine the body’s cellular bioenergetics, particularly the mitochondria.
Inflammation Vs. Energy Production in Lyme Disease
As previously discussed in a previously published article in this blog, titled Beyond Energy Production – Mitochondria Drive Cellular Function, the mitochondria generate adenosine triphosphate (ATP), the cell’s energy source, via oxidative phosphorylation. They also play another key role as sentinels of health, a role that is not frequently discussed outside the mitochondrial research community.
When the immune system detects an assault or stressor, such as Borrelia burgdorferi, it initiates defensive action to protect the body by producing reactive oxygen species (ROS) and nitric oxide to create an inhospitable environment for the invading bacteria.
This process is typically short-lived and resolves after the bacteria are eliminated. However, during periods of significant stress and assault, the defensive action can remain active. This process results in low-grade systemic inflammation and has been defined by Robert K. Naviaux, PhD, MD, professor of Medicine, Pediatrics and Pathology at UC San Diego School of Medicine, and founder of the Naviaux Mitochondrial Lab at UCSD, as unresolved Cell Danger Response (CDR).
The image below shows a simple encapsulation of his theory of what happens when the cell gets stuck in CDR and cannot complete the healing cycle, and when the cell can complete the healing cycle.
When systemic inflammation is unchecked, cells undergo an immunometabolic shift. Instead of using efficient mitochondrial pathways to generate energy, they switch to less efficient glycolytic pathways. This process creates metabolic dysregulation, a downward bioenergetics cycle, ultimately resulting in the debilitating exhaustion reported by individuals with Lyme disease. (Taylor, 2026)
The Diagnostic Challenge - Identifying the Great Imitator
Navigating a Lyme disease diagnosis is often complicated by diagnostic roadblocks. In many instances, individuals do not present with the classic bullseye rash (erythema migrans), making early detection difficult for clinicians.
The graphic below demonstrates some of the key symptoms of this extremely challenging disease.
When an active infection goes undetected and unresolved, it can lead to diagnostic confusion and mimic other complex conditions, including Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). In these instances, selecting the appropriate immune-based treatment becomes difficult because the core driver (Borrelia burgdorferi) is not considered in the differential diagnosis
Restoring Balance in Lyme Disease
Lyme disease rarely travels alone. Co-infections such as Bartonella, Babesia, and Anaplasmosis are common companions to Borrelia burgdorferi, each adding to the inflammatory burden in a system that is already struggling to keep up.
When these pathogens compound each other, and when early diagnosis is missed, the body is pushed further in the downward bioenergetics spiral described above. This co-morbid effect forces mitochondria to fuel an active immune response and everyday cellular function with a fraction of their usual capacity, disrupting the body’s bioenergetics and contributing to hypersensitivity to treatments in individuals with multiple vector-borne infections.
Addressing whole-body exhaustion at the cellular level is why mitochondrial support may play a central role in a Lyme recovery approach, rather than a peripheral one.
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References
- Barriales, D., Martín-Ruiz, I., Carreras-González, A., Montesinos-Robledo, M., Azkargorta, M., Iloro, I., Escobés, I., Martín-Mateos, T., Atondo, E., Palacios, A., Gonzalez-Lopez, M., Bárcena, L., Cortázar, A. R., Cabrera, D., Peña-Cearra, A., van Liempd, S. M., Falcón-Pérez, J. M., Pascual-Itoiz, M. A., Flores, J. M., Abecia, L., … Anguita, J. (2021). Borrelia burgdorferi infection induces long-term memory-like responses in macrophages with tissue-wide consequences in the heart. PLOS Biology, 19(1), e3001062. https://doi.org/10.1371/journal.pbio.3001062
- Dashore, J. A., Dashore, B., McMahon, S., & Shoemaker, R. (2025). Autism spectrum disorders and Lyme disease: Exploring shared neuro-inflammatory and immune pathways. Medical Research Archives, 13(11). https://doi.org/10.18103/mra.v13i11.7019
- Kerstholt, M., Brouwer, M., Te Vrugt, M., Oosting, M., Netea, M. G., & Joosten, L. A. B. (2022). Borrelia burgdorferi inhibits NADPH-mediated reactive oxygen species production through the mTOR pathway. Ticks and Tick-borne Diseases, 13(4), 101943. https://doi.org/10.1016/j.ttbdis.2022.101943
- Molnar, T., Lehoczki, A., Fekete, M., Varnai, R., Zavori, L., Erdo-Bonyar, S., Simon, D., Berki, T., Csecsei, P., & Ezer, E. (2024). Mitochondrial dysfunction in long COVID: Mechanisms, consequences, and potential therapeutic approaches. GeroScience, 46(4), 5267–5286. https://doi.org/10.1007/s11357-024-01165-5
- Nguyen, C., Byne, A., Birkaya, B., & Luchini, A. (2025). Extracellular vesicles derived from Borrelia burgdorferi leads to prolonged neuroinflammation in Lyme disease. Journal of Student-Scientists’ Research, 7. https://doi.org/10.13021/jssr2025.5264
- Peacock, B. N., Gherezghiher, T. B., Hilario, J. D., & Kellermann, G. H. (2015). New insights into Lyme disease. Redox Biology, 5, 66–70. https://doi.org/10.1016/j.redox.2015.03.002
- Taylor, P. A. (2026). Mitochondrial dysfunction and immunometabolic reprogramming in Lyme disease associated fatigue. Undergraduate Library Research Awards, 1. https://digitalcommons.lmu.edu/ulra/awards/2026/1