Mitochondrial DNA and Toll-Like Receptor-9 Are Associated With Mortality in Critically Ill Patients

Crit Care Med. 2015 Dec;43(12):2633-41. doi: 10.1097/CCM.0000000000001311.


Objectives: Despite underlying pathologies leading to ICU admittance are heterogeneous, many patients develop a systemic inflammatory response syndrome often in the absence of microbial pathogens. Mitochondrial DNA that shows similarities to bacterial DNA may be released after tissue damage and activates the innate immune system by binding to toll-like receptor-9 on immune cells. The aim of this study was to analyze whether levels of mitochondrial DNA are associated with 30-day survival and whether this predictive value is modified by the expression of its receptor toll-like receptor-9.

Design: Single-center, prospective, observational study.

Setting: A tertiary ICU in a university hospital.

Patients: Two hundred twenty-eight consecutive patients admitted to a medical ICU between August 2012 and August 2013.

Interventions: None.

Measurements and main results: Blood was taken within 24 hours after ICU admission, and the levels of circulating mitochondrial DNA were quantified by real-time polymerase chain reaction. Toll-like receptor-9 expression in monocytes was measured by flow cytometry. Median acute physiology and chronic health evaluation II score was 20, and 30-day mortality was 25%. Median mitochondrial DNA levels at admission were significantly higher in nonsurvivors when compared with survivors (26.9, interquartile range = 11.2-60.6 ng/mL vs 19.7, interquartile range = 9.5-34.8 ng/mL; p < 0.05). Patients with plasma levels of mitochondrial DNA in the highest quartile (mitochondrial DNA > 38.2 ng/mL) had a 2.6-fold higher risk (p < 0.001) of dying, independently of age, gender, diagnosis, and acute physiology and chronic health evaluation II score. Mitochondrial DNA improved the c-statistic of acute physiology and chronic health evaluation II score (p < 0.05) and showed enhancement in individual risk prediction indicated by a net reclassification improvement of 32.3% (p < 0.05). Stratification of patients according to toll-like receptor-9 expression above/below median demonstrated that only patients with high expression of toll-like receptor-9 showed an increased risk associated with increased mitochondrial DNA levels (odds ratio, 2.7; p < 0.01), whereas circulating mitochondrial DNA was not associated with mortality in patients with low toll-like receptor-9 expression (odds ratio, 1.1; p = 0.98).

Conclusions: Circulating levels of mitochondrial DNA at ICU admission predict mortality in critically ill patients. This association was in particular present in patients with elevated toll-like receptor-9 expression.

Publication types

  • Observational Study

MeSH terms

  • Age Factors
  • Aged
  • Critical Illness / mortality*
  • DNA, Mitochondrial / biosynthesis*
  • Female
  • Flow Cytometry
  • Hospital Mortality
  • Hospitals, University
  • Humans
  • Intensive Care Units / statistics & numerical data*
  • Male
  • Middle Aged
  • Odds Ratio
  • Predictive Value of Tests
  • Prospective Studies
  • Real-Time Polymerase Chain Reaction
  • Severity of Illness Index
  • Sex Factors
  • Toll-Like Receptor 9 / biosynthesis*


  • DNA, Mitochondrial
  • Toll-Like Receptor 9