The Mechanism Behind Cytokine Storm and Mitochondrial Dysfunction

The current urge to treat proinflammatory conditions such as the Covid-19 induced cytokine storm has positioned mitochondrial function in the central stage of scientific research. Indeed, impaired immune responses, elevated oxidative stress, and increased proinflammatory cytokines create a vicious cycle in which mitochondrial dysfunction prevails. Furthermore, this continuous state of inflammation leads to oxidative/inflammatory diseases like neurodegenerative disorders, cardiometabolic conditions, inflammatory bowel syndrome, and complications derived from Covid-19 pathology. Preserving mitochondrial function is possible by reducing oxidative stress, improving metabolic processes, and reducing the inflammatory response. Furthermore, the scientific literature supports the efficacy of melatonin, alone or in combination with micronutrients, to support mitochondrial function, reduce oxidative stress and prevent cytokine storms.

What is a Cytokine storm?

Cytokine storm is a medical term currently associated with the Covid-19 pathophysiology but is also present in conditions like rheumatoid arthritis and other viruses. This term describes a severe and damaging immune reaction accompanied by unlimited and uncontrolled production of proinflammatory cytokines.

The mechanism that starts the cytokines storm is when many white blood cells, such as neutrophils, macrophages, and mast cells, release proinflammatory cytokines. This first mechanism, when modulated, coordinates an effective immune response and triggers a regulating inflammatory process that detects and resolves the infection. However, in a cytokine storm, the autoinduction of IL-1, which is capable of expressing its own gene and upregulating the production of IL-6 and TNF-a.

Furthermore, IL-6 creates a proinflammatory milieu by stimulating the differentiation of B-lymphocytes and T- cells as immunoglobulin-producing cells. In addition, TNF-a is responsible for the exaggerated secretion of proinflammatory cytokines by T-cells and is a potent precursor of the NFkB pathway. Consequently, the activation of the NFkB cascade activates the secretion of IL-1β and TNF-a, creating a pro-oxidant state.

Cytokine storm and mitochondrial dysfunction

Mitochondria have multiple essential functions in the body: 

ATP synthesis, calcium homeostasis, apoptosis, and reactive oxygen species production. Also, ATP synthesis depends on an intricate metabolic chain mediated by enzymes, which function is upregulated by cofactors (vitamins and minerals). Furthermore, an altered mitochondrial structure will affect its capacity to produce energy, leading to increased production of ROS and contributing to the development of inflammation.

Inflammatory mechanisms altering mitochondrial function:

• Elevated circulatory proinflammatory cytokines are the cornerstone of mitochondrial dysfunction and vice versa, creating a vicious cycle of inflammation and elevated ROS production. Furthermore, an upregulated production of ROS leads to mitochondrial proteins, lipids, and membrane damage, meaning that mitochondrial DNA (mtDNA) is directly affected by ROS. In addition, the excessive synthesis of iNOS during mitochondrial inflammation upregulates NO production and leads to reactive nitrogen species (RNS) production. Consequently, these mechanisms affect ATP production by interfering with the electron transport chain (ETC).
• The upregulation of inflammatory processes due to elevated TNF-a and IL-1 concentration affects the enzymatic action of essential metabolic molecules, such as pyruvate dehydrogenase (PDH) and complex I and II. This inhibition has been reported in several cell types like cardiomyocytes, myocytes, and hepatocytes.
• In addition, lipopolysaccharide (LPS) downregulates complex I, III, and IV of the ETC in hepatocytes, altering mitochondrial energy production.
• Research reports that elevated concentration of TNF-a downregulates mitochondrial biogenesis by reducing the expression of peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α).
• Increased production of ROS leads to the activation of the NOD-, LRR- and pyrin domain-containing 3 (NLRP3) inflammasome, which acts as a sensor of mitochondrial dysfunction and is an activator of innate immune pathways. Furthermore, NLRP3 initiates Il-1B activation, resulting in reduced mitochondrial membrane potential, elevated ROS production, and a lower ATP synthesis. 

An elevated inflammatory response, uncontrolled immune mechanisms, and mitochondrial dysfunction create a vicious cycle that promotes a cytokine storm. The mechanisms described in this article are pathways that can be downregulated using anti-inflammatory bioactive compounds such as melatonin. Furthermore, anti-oxidant vitamins and minerals act as metabolic enzymes and transport proteins cofactors to ensure adequate energy production and reduce ROS concentration. – Ana Paola Rodríguez Arciniega, MS.

References:

Martín Giménez, Virna Margarita et al. “Potential Effects of Melatonin and Micronutrients on Mitochondrial Dysfunction during a Cytokine Storm Typical of Oxidative/Inflammatory Diseases.” Diseases (Basel, Switzerland) vol. 9,2 30. 14 Apr. 2021, doi:10.3390/diseases9020030

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