Circulating mitochondrial DNA is an early indicator of severe illness and mortality from COVID-19

JCI Insight. 2021 Feb 22;6(4):e143299. doi: 10.1172/jci.insight.143299.


BackgroundMitochondrial DNA (MT-DNA) are intrinsically inflammatory nucleic acids released by damaged solid organs. Whether circulating cell-free MT-DNA quantitation could be used to predict the risk of poor COVID-19 outcomes remains undetermined.MethodsWe measured circulating MT-DNA levels in prospectively collected, cell-free plasma samples from 97 subjects with COVID-19 at hospital presentation. Our primary outcome was mortality. Intensive care unit (ICU) admission, intubation, vasopressor, and renal replacement therapy requirements were secondary outcomes. Multivariate regression analysis determined whether MT-DNA levels were independent of other reported COVID-19 risk factors. Receiver operating characteristic and area under the curve assessments were used to compare MT-DNA levels with established and emerging inflammatory markers of COVID-19.ResultsCirculating MT-DNA levels were highly elevated in patients who eventually died or required ICU admission, intubation, vasopressor use, or renal replacement therapy. Multivariate regression revealed that high circulating MT-DNA was an independent risk factor for these outcomes after adjusting for age, sex, and comorbidities. We also found that circulating MT-DNA levels had a similar or superior area under the curve when compared against clinically established measures of inflammation and emerging markers currently of interest as investigational targets for COVID-19 therapy.ConclusionThese results show that high circulating MT-DNA levels are a potential early indicator for poor COVID-19 outcomes.FundingWashington University Institute of Clinical Translational Sciences COVID-19 Research Program and Washington University Institute of Clinical Translational Sciences (ICTS) NIH grant UL1TR002345.

Keywords: COVID-19; Complement; Immunology; Mitochondria.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aged
  • Aged, 80 and over
  • Biomarkers / blood
  • COVID-19 / diagnosis*
  • COVID-19 / mortality
  • COVID-19 / therapy
  • COVID-19 / virology
  • Cell-Free Nucleic Acids / blood*
  • DNA, Mitochondrial / blood*
  • Female
  • Follow-Up Studies
  • Hospital Mortality
  • Humans
  • Intensive Care Units / statistics & numerical data
  • Male
  • Middle Aged
  • Prospective Studies
  • ROC Curve
  • Renal Replacement Therapy / statistics & numerical data
  • Respiration, Artificial / statistics & numerical data
  • Risk Factors
  • SARS-CoV-2 / isolation & purification
  • Severity of Illness Index*
  • Vasoconstrictor Agents / therapeutic use


  • Biomarkers
  • Cell-Free Nucleic Acids
  • DNA, Mitochondrial
  • Vasoconstrictor Agents