Understanding mitochondrial dysfunction in Long COVID
While mitochondria play a role in inflammation and cellular signaling, the primary role of these organelles is to produce energy. The so-called powerhouses of the cell control cellular respiration, in which oxygen and metabolites/substrates are converted to adenosine triphosphate (ATP), the energy currency of the cell. Energy is stored in the high-energy phosphate bond of ATP. As that chemical bond is broken and converted to energy, ATP loses one of its three phosphates, becoming adenosine diphosphate (ADP). ADP can then be phosphorylated again to regenerate ATP in a cyclical process similar to recharging a battery. The high-energy phosphate is shuttled back to the mitochondria where it can combine with creatine, producing phosphocreatine. The phosphocreatine can subsequently lend its phosphate to ADP to rapidly produce ATP.
Metabolites for cellular respiration include fatty acids, from triglycerides and other lipids, pyruvate, produced from glucose during glycolysis, and amino acids, from proteins. While metabolism of these molecules dominates cellular energetics, there are other ways to generate ATP. Although it is less efficient than cellular respiration, glycolysis is another metabolic pathway that can rapidly produce ATP within the cell cytoplasm without the need for oxygen.
Mitochondrial dysfunction involves energetic and lipid dysregulation, as well as inflammation. It underlies many diseases and conditions, from those affecting the central nervous system, to the muscle, heart, and kidneys. Cardiopulmonary testing has shown that impaired exercise tolerance and post-exercise fatigue in Long COVID patients may be driven by skeletal muscle abnormalities, suggesting phosphocreatine recycling is delayed. This leads to impaired oxidative capacity, as well as an inability for the cell to keep up with energetic demand during exertion, especially in tissues with a high metabolic demand like muscles. Rate of recovery of phosphocreatine is a good measure of mitochondrial oxidative capacity and correlates with measures of exercise tolerance (e.g., six-minute walk test).
Viruses are known to hijack mitochondrial function, exploiting the cell for the energy they need to metabolize proteins, generate new viral particles, and replicate, as well as evade antiviral surveillance by the immune system. Preclinical and clinical work has shown that during the acute phase of COVID-19 infection, the virus upregulates glycolysis to rapidly produce more virus particles and downregulates more-efficient oxidative phosphorylation pathways. This shift throws the cell into a state of crisis, in which its functionality degrades, increasing oxidative stress (imbalance of between oxidants and antioxidants in favor of oxidants), inflammation, and immune impairment, as well as reducing muscle oxidative capacity and function.
To enter a cell, SARS-CoV-2 exploits the angiotensin-converting enzyme 2 (ACE2) receptor. This transmembrane protein is key to regulation of the renin-angiotensin-aldosterone system that regulates blood volume and systemic vascular resistance, but it also plays a role in mitochondrial functions. Disruption of this receptor impacts cell energetics and antioxidant response, as well as vascular perfusion (i.e., blood flow through the circulatory system to organs).
Although SARS-CoV-2 is a new virus, it modulates existing mechanisms that are well elucidated and studied extensively (e.g., viral entry via the ACE2 receptor). The difference with SARS-CoV-2 is the multitude of mechanisms it modulates, simultaneously impacting the ACE2 receptor and downstream biology, vascular perfusion and endothelial function, oxidative stress, proinflammatory processes, immune function and surveillance, and cellular bioenergetics.
