Mitochondrial DNA Poly-C length heteroplasmy as a marker for risk of critical COVID-19

Mitochondria play a central role in the innate and acquired response against viral infections. Common mtDNA variants have been associated with severe COVID-19 and mtDNA depletion. A poly C length variation has been associated with mtDNA instability and increased risk for several diseases. We studied 482 patients who required treatment in the intensive care unit and age matched population controls. The 16184-16193 poly-C and 514-523 CA-repeats were determined by fluorescent capillary electrophoresis and Sanger sequencing of PCR fragments. We found a significantly higher frequency of 16184-16193 mtDNA poly-C heteroplasmy in patients aged ≤60 compared to patients aged >60 years. Poly-C heteroplasmy did not differ between the age control groups. Poly-C heteroplasmy was associated with the presence of the 16223 T allele, that was associated with the risk of critical COVID-19 at ≤60 years. In Conclusion, heteroplasmy in the poly-C tract of the mtDNA control region might be a marker for critical COVID-19. The 16184-16193 heteroplasmy was linked to the 16223 T allele, that was significantly increased among patients aged ≤60 years. This finding requires validation in other cohorts and to determine the functional link between length variation in the mitochondrial DNA control sequence and risk of severe SARS-CoV-2 disease.