Biochem Presentation on the introduction to biomolecules.pptx

Long COVID and Mitochondrial Dysregulation

1. Long COVID and Mitochondrial Dysregulation Taneecia Natarajan

2. Background What is Long Covid? Long COVID is an often debilitating illness that occurs in at least 10% of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. Most common symptoms: Fatigue Post-exertional malaise Cognitive dysfunction Breathlessness Chest pain and tachycardia Significance Current explanations lack a clear mechanistic basis However, the most common reported symptom of long COVID is fatigue and the overall symptom picture resembles that of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) Investigating cellular metabolism and mitochondrial health could explain why these symptoms persist and develop treatments Figure reproduced from Davis et al., 2023. Nature Reviews Microbiology. (Borland Madsen et al., 2024)

3. Prompt Evidence The most common reported symptom of long COVID is fatigue and the overall symptom picture resembles that of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), which is often triggered by a viral infection. Fatigue can be described as a lack of energy, and the mitochondria plays a key role in energy production In long COVID, mitochondrial dysfunction is suspected to play a central role. Damage to mitochondria leads to reduced ATP production, contributing to persistent fatigue. Why do people with long COVID experience common symptoms of neurological dysfunction such as persistent fatigue and myalgic encephalomyelitis/chronic fatigue syndrome? Could the cause be linked to mitochondrial dysfunction and impaired cellular energy production?”

4. Basic Overview of Mitochondrial Function The primary role of the mitochondria is to generate energy Mitochondria convert glucose, fatty acids, and amino acids into ATP via aerobic respiration. Two main stages of energy production: TCA cycle (Krebs cycle): Generates high-energy electron carriers (NADH, FADH₂). Electron Transport Chain (ETC): Uses electron carriers to produce ATP through oxidative phosphorylation. Mitochondria also regulate: Calcium homeostasis for cellular signaling (e.g., muscle contraction, neural activity). Oxidative stress by controlling ROS production and detoxification. Programmed cell death (apoptosis) in response to cellular damage. (Martínez-Reyes & Chandel, 2020) Figure reproduced from Martínez-Reyes & Chandel, 2020. Nature Communications.

5. How SARS-CoV-2 Affects Mitochondria SARS-CoV-2 has been shown to localize to the mitochondria during infection SARS-CoV-2 proteins (such as ORF-9b) target mitochondrial antiviral signaling (MAVS) proteins, compromising mitochondrial integrity. This suppression of MAVS disrupts the normal activation of IRF3 and NF-κB via RIG-I signaling, preventing a robust antiviral interferon response. Cytosolic mtDNA activates the cGAS-STING pathway, which produces cGAMP, triggering an inflammatory cascade and excessive production of type I interferons and proinflammatory cytokines. These disruptions impair ATP production, elevate reactive oxygen species (ROS), and reduce the cell’s capacity to respond to metabolic stress. (Madsen et al., 2024) Figure reproduced from Madsen et al., 2024. NPJ Metabolic Health and Disease.

6. Biochemical Pathways Impacted Damage to the mitochondrial inner membrane leads to inefficient electron transfer through the ETC complexes. This leakage produces excess reactive oxygen species (ROS) Long COVID patients show reduced availability of NAD⁺ and FAD. Without them, the TCA cycle slows down, limiting the number of electrons supplied to the ETC and further decreasing ATP production. Proinflammatory cytokines alter gene expression, down regulating genes involved in mitochondrial replication and metabolic regulation. These combined disruptions result in widespread energy deficits and oxidative stress. This provides a biochemical explanation for fatigue, brain fog. (Martínez et al., 2024) Figure reproduced from Martínez et al., 2024. Journal of Proteome Research.

7. Experimental Evidence Researchers performed multiplatform mass spectrometry-based metabolomics on plasma from long COVID patients vs. healthy controls. Found significant disruptions in TCA cycle intermediates : ↓ Malate, α-ketoglutarate, citrate → impaired mitochondrial respiration. Observed depletion of key amino acids feeding the mitochondria: ↓ Glutamine, phenylalanine, isoleucine → reduced metabolic flexibility. Detected increased oxidative stress biomarkers: ↑ α-ketobutyric acid, β-hydroxybutyrate → indicating redox imbalance. Metabolic shifts correlated with symptom severity and patients with the most pronounced biochemical changes had worse fatigue and brain fog. (Martínez et al., 2024) Figure reproduced from Martínez et al., 2024. Journal of Proteome Research.

8. Experimental Evidence Researchers assessed mitochondrial dysfunction in long COVID using Circulating cell-free mitochondrial DNA (ccf-mtDNA), mitochondrial fusion/fission proteins (MFN1, DRP1), and electron microscopy of patient mitochondria Findings: ↓ ccf-mtDNA in long COVID suggesting impaired mitophagy and reduced mitochondrial turnover ↓ MFN1 (fusion) and ↑ DRP1 (fission) indicating excessive mitochondrial fragmentation EM imaging showed swollen mitochondria, disrupted cristae, and irregular outer membranes Dysfunctional mitochondria = less ATP, affecting energy-hungry tissues Explains fatigue, brain fog, and post-exertional malaise (Szögi et al., 2025) Figure reproduced from Szögi et al., 2025. GeroScience.

9. Conclusions Long COVID is characterized by persistent fatigue, brain fog, and post-exertional malaise, which can be traced to disrupted cellular energy production. Biochemical evidence points to mitochondrial dysfunction as a central mechanism, characterized by impaired ATP production, redox imbalance, TCA cycle disruption, and altered mitochondrial dynamics. Martínez et al., 2024 provided metabolomic data showing reduced TCA intermediates, amino acid depletion, and oxidative stress markers, directly linking mitochondrial metabolism to symptom severity. Lehoczki et al., 2024 identified structural and molecular biomarkers of mitochondrial damage, including reduced ccf-mtDNA and imbalanced fusion/fission protein expression, supporting long-term mitochondrial stress. Therapeutic research is exploring: NAD⁺ precursors (e.g., NMN, NR) to restore mitochondrial redox balance CoQ10 and mitochondrial antioxidants to reduce oxidative stress Anti-inflammatory therapies targeting IL-6 and TNF-α signaling Lifestyle interventions like pacing, gentle aerobic exercise, and nutrition to support mitochondrial health

10. References Martínez, S., Albóniga, O. E., López-Huertas, M. R., et al. (2024). Reinforcing the evidence of mitochondrial dysfunction in long COVID patients using a multiplatform mass spectrometry-based metabolomics approach. Journal of Proteome Research, 23 (8), 3025–3040. https://doi.org/10.1021/acs.jproteome.3c00860 Madsen, H. B., Durhuus, J. A., Andersen, O., et al. (2024). Mitochondrial dysfunction in acute and post-acute phases of COVID-19 and risk of non-communicable diseases. NPJ Metabolic Health and Disease, 2 (1), 36. https://doi.org/10.1038/s44324-024-00038-x Martínez-Reyes, I., & Chandel, N. S. (2020). Mitochondrial TCA cycle metabolites control physiology and disease. Nature Communications, 11 , 102. https://doi.org/10.1038/s41467-019-13668-3 Szögi, T., Borsos, B. N., Masic, D., Radics, B., Bella, Z., Bánfi, A., Ördög, N., Zsiros, C., Kiricsi, Á., Pankotai-Bodó, G., Kovács, Á., Paróczai, D., Botkáné, A. L., Kajtár, B., Sükösd, F., Lehoczki, A., Polgár, T., Letoha, A., Pankotai, T., & Tiszlavicz, L. (2024). Novel biomarkers of mitochondrial dysfunction in Long COVID patients. GeroScience, 47 , 2245–2261. https://doi.org/10.1007/s11357-024-01519-0