Marylou VSolbrig, Professor of Medicine (Neurology) and Medical Microbiology (retired), University of Manitoba
Submitted November 30, 2020
Since Dr. Nath’s Special Editorial on Long-Haul COVID1 in the September issue of Neurology, there has been increasing media coverage of athletes, or previously very fit individuals, struggling with the exhaustion of long-haul COVID. The difficulties faced by runners, cyclists, even children who attended ballet classes 4 days/week or dancing and aikido lessons 5 days/week2 have been reported in sports and athletic magazines, newspapers, and news shows.
Long-haul COVID resembles, to some degree, “overtraining syndrome”, in that disordered metabolism or energy utilization may be common to both. Overtraining syndrome is the maladaptive response to excessive exercise training characterized by under- or impaired sport performance, persistent fatigue, mood alterations, disturbed sleep, neuroendocrine changes.3 Could mitochondria have a role in pathogenesis of long-haul COVID? Mitochondrial DNA (mtDNA) stress is also a cell-intrinsic stimulus for antiviral signaling. Humans have a DNA sensing and defense system to cytosolic DNA exposure, such that virus-derived cytosolic DNA as well as self-DNA can trigger immune responses.4
A common feature of + strand RNA viruses is that virus replication takes place on host intracellular membranes. For coronaviruses it is on mitochondria, as shown by localization of SARS-COV-2 open reading frame proteins to mitochondria.5 Mitochondria, upon viral infection, would leak mtDNA into cytoplasm and extracellular space. Systems for monitoring mtDNA homeostasis, for example, the integrity of intracellular and extracellular mtDNA, work together with canonical virus sensing systems to generate an mtDNA inflammasome and stimulation of interferon genes.4
Although mitochondrial cytopathy does not explain how acute becomes long-term illness, mitochondria—fundamental to life—may present new paradigms for disease understanding. Mitochondrial mechanisms related to striatal muscle may generalize to smooth and cardiac muscle and capture some of the autonomic features of long-haul COVID. Mechanisms generalizable to the brain may further elucidate cognitive and attention features of long-haul COVID.
Disclosure
The author reports no relevant disclosures. Contact journal@neurology.org for full disclosures.
References
Nath A. Long-Haul COVID. Neurology 2020;95:559-560.
Tuller, D. At 12, She’s a Covid ‘Long Hauler’[online]. Available at: nytimes.com. Accessed Oct 22, 2020.
Kreher JB, Schwartz JB. Overtraining Syndrome: A practical guide. Sports Health 2012;4:128-138.
West AP, Khoury-Hanold W, Staron M, et al. Mitochondrial DNA stress primes the antiviral innate immune response. Nature 2015;520:553-557.
Singh KK, Chaubey G, Chen JY, Suravajhala P. Decoding SARS-CoV-2 hijacking of host mitochondria in COVID-19 pathogenesis. Am J Physiol Cell Physiol 2020;319:C258-C267.
Since Dr. Nath’s Special Editorial on Long-Haul COVID1 in the September issue of Neurology, there has been increasing media coverage of athletes, or previously very fit individuals, struggling with the exhaustion of long-haul COVID. The difficulties faced by runners, cyclists, even children who attended ballet classes 4 days/week or dancing and aikido lessons 5 days/week2 have been reported in sports and athletic magazines, newspapers, and news shows.
Long-haul COVID resembles, to some degree, “overtraining syndrome”, in that disordered metabolism or energy utilization may be common to both. Overtraining syndrome is the maladaptive response to excessive exercise training characterized by under- or impaired sport performance, persistent fatigue, mood alterations, disturbed sleep, neuroendocrine changes.3 Could mitochondria have a role in pathogenesis of long-haul COVID? Mitochondrial DNA (mtDNA) stress is also a cell-intrinsic stimulus for antiviral signaling. Humans have a DNA sensing and defense system to cytosolic DNA exposure, such that virus-derived cytosolic DNA as well as self-DNA can trigger immune responses.4
A common feature of + strand RNA viruses is that virus replication takes place on host intracellular membranes. For coronaviruses it is on mitochondria, as shown by localization of SARS-COV-2 open reading frame proteins to mitochondria.5 Mitochondria, upon viral infection, would leak mtDNA into cytoplasm and extracellular space. Systems for monitoring mtDNA homeostasis, for example, the integrity of intracellular and extracellular mtDNA, work together with canonical virus sensing systems to generate an mtDNA inflammasome and stimulation of interferon genes.4
Although mitochondrial cytopathy does not explain how acute becomes long-term illness, mitochondria—fundamental to life—may present new paradigms for disease understanding. Mitochondrial mechanisms related to striatal muscle may generalize to smooth and cardiac muscle and capture some of the autonomic features of long-haul COVID. Mechanisms generalizable to the brain may further elucidate cognitive and attention features of long-haul COVID.
Disclosure
The author reports no relevant disclosures. Contact journal@neurology.org for full disclosures.
References