SARS-CoV-2 Propagation and Pathology and Mitochondrial Genetics
Abstract
Background: There is striking variability in the individual pathology of COVID-19 patients. Individuals with severe COVID-19 have 60-fold higher SARS-CoV-2 RNA loads than patients with mild disease. Furthermore, mildly affected patients clear the virus by ~7 days post-presentation while severely affected patients maintain high viral RNA levels up to 25 days post-presentation. Recent studies have shown that SARS-CoV-2-encoded proteins interact with a wide array of host mitochondrial proteins, indicating that the regulation of mitochondrial function must be a critical factor in successful viral infection. Therefore, if we could modulate mitochondrial function, we might be able to reduce the severity of SARS-CoV-2 infection to the level of a common cold. SARS-CoV-2 is the viral infectious agent that causes the pandemic disease COVID-19. It is a coronavirus, in the same class as a number of viruses that cause the common cold. However, while in most patients SARS-CoV-2 causes a mild cold-like respiratory infection, in other patients the virus causes a severe respiratory disease that can last for prolonged periods, cause extreme inflammation, and in about 2% of cases kill the patient. While the reaction of patients to SARS-CoV-2 is highly variable, the virus itself is highly genetically stable. Hence, the variable pathology of COVID-19 is not the virus, so it must be the patient. SARS-CoV-2 is most deleterious to men, the elderly, and individuals who are obese, diabetic, or have cardiovascular disease. This sensitivity signature is precisely the same signature that we have discovered for patients with mitochondrial genetic disease. Since SARS-CoV-2 strongly affects mitochondrial function and differences in mitochondrial function have the same range of patient sensitivities as COVID-19, it follows that individual differences in mitochondrial variation may be the basis of the differential toxicity of SARS-CoV-2. The mitochondrion is known as the “power plant” of the cell generating ~90% of all of our energy. Mitochondria generate energy by oxidizing the calories in our food with the oxygen we breathe, and storing the energy in ATP. As a byproduct of respiration, the mitochondrion also generate oxygen radicals, the smoke of the mitochondrial power plant. Our mitochondria are the descendants of ancient bacteria that entered our type of cell a couple of billion years ago. As a carryover from their original independent lives, the mitochondria are unique in having their own DNA, the mitochondrial DNA (mtDNA). Today the mtDNA carries the most critical genes for making energy. In a very real sense, the modern mtDNA is the wiring diagram of the mitochondrial power plant. The mtDNA is unique in that it is located within the mitochondrion in the cytoplasm of the cell, present in hundreds to thousands of copies per cell, and inherited exclusive from the mother. We demonstrated over 30 years ago that mutations in the mtDNA can cause inherited disease, and it is now clear that mtDNA mutations can cause a wide spectrum of common clinical problems including obesity, diabetes, and cardiovascular disease. Moreover, milder mtDNA mutations preferentially affect males, and mtDNA mutations accumulate as we age causing an age-related decline in mitochondrial function. Finally, mtDNA sequences are highly variable between individuals, and this results in many of the physiological differences that are so apparent between people: some heavy some thin, some hot some cold, some sensitive to infection some not. Rationale: The concepts about mitochondrial genetics and its relevance to common diseases is the result of the past 40+ years of mitochondrial research by our laboratory. The fact that nearly half of the cellular proteins that SARS-CoV-2 proteins bind are involved in energy metabolism and the parallelism between mitochondrial variation, clinical symptoms, and COVID-19 sensitivity is striking. Hence, it seems likely
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110128
Entities
People
- Douglas C Wallace
Organizations
- United States Army