Circulating Mitochondrial DNA in Patients in the ICU as a Marker of Mortality: Derivation and Validation
Open accessAbstract
BACKGROUND: Mitochondrial DNA (mtDNA) is a critical activator of inflammation and the innate immune system. However, mtDNA level has not been tested for its role as a biomarker in the intensive care unit (ICU). We hypothesized that circulating cell-free mtDNA levels would be associated with mortality and improve risk prediction in ICU patients. METHODS AND FINDINGS: Analyses of mtDNA levels were performed on blood samples obtained from two prospective observational cohort studies of ICU patients (the Brigham and Women's Hospital Registry of Critical Illness [BWH RoCI, n = 200] and Molecular Epidemiology of Acute Respiratory Distress Syndrome [ME ARDS, n = 243]). mtDNA levels in plasma were assessed by measuring the copy number of the NADH dehydrogenase 1 gene using quantitative real-time PCR. Medical ICU patients with an elevated mtDNA level (≥3,200 copies/µl plasma) had increased odds of dying within 28 d of ICU admission in both the BWH RoCI (odds ratio [OR] 7.5, 95% CI 3.6-15.8, p = 1×10(-7)) and ME ARDS (OR 8.4, 95% CI 2.9-24.2, p = 9×10(-5)) cohorts, while no evidence for association was noted in non-medical ICU patients. The addition of an elevated mtDNA level improved the net reclassification index (NRI) of 28-d mortality among medical ICU patients when added to clinical models in both the BWH RoCI (NRI 79%, standard error 14%, p<1×10(-4)) and ME ARDS (NRI 55%, standard error 20%, p = 0.007) cohorts. In the BWH RoCI cohort, those with an elevated mtDNA level had an increased risk of death, even in analyses limited to patients with sepsis or acute respiratory distress syndrome. Study limitations include the lack of data elucidating the concise pathological roles of mtDNA in the patients, and the limited numbers of measurements for some of biomarkers. CONCLUSIONS: Increased mtDNA levels are associated with ICU mortality, and inclusion of mtDNA level improves risk prediction in medical ICU patients. Our data suggest that mtDNA could serve as a viable plasma biomarker in medical ICU patients.
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Extracellular mitochondria have been identified in damaged tissues, diverse inflammatory conditions, and in the blood of critical care patients.
“Extracellular mitochondria have been identified in damaged tissues (8, 18–20); diverse inflammatory conditions (11, 12, 14, 21–24); and in the blood of critical care patients (22).”
From Autoantibodies in Systemic Lupus Erythematosus Target Mitochondrial RNA (2019) · cites this paper as [22]
The citation to this paper is attached to the claim about blood of critical care patients. The Discussion reports circulating cell-free mitochondrial DNA in ICU patients, and the Methods describe measuring DNA copies in plasma. That supports the patient and blood setting, but not the identification of extracellular mitochondria as intact organelles. (LLM, conf=0.88)
Experimental — accuracy not yet measuredExtracellular mtDNA is associated with various pathologies, including trauma, burn injury, cancer, and rheumatoid arthritis.
“As extracellular mtDNA is reportedly associated with various pathologies, including trauma25,26, burn injury27, cancer28 and rheumatoid arthritis17,29”
From Anti-mitochondrial autoantibodies in systemic lupus erythematosus and their association with disease manifestations (2019) · cites this paper as [26]
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- Authors
- Nakahira, K., Kyung, S.-Y., Rogers, A. J., Gazourian, L., Youn, S., Massaro, A. F., Quintana, C., Osorio, J. C., Wang, Z., Zhao, Y., Lawler, L. A., Christie, J. D., Meyer, N. J., Causland, F. R. M., Waikar, S. S., Waxman, A. B., Chung, R. T., Bueno, R., Rosas, I. O., Fredenburgh, L. E., Baron, R. M., Christiani, D. C., Hunninghake, G. M., & Choi, A. M. K.
- Affiliations
- Brigham and Women's Hospital (US)
- Harvard University (US)
- University of Pennsylvania (US)
- Corresponding author
- Choi, Augustine M. K.
- ORCID
- Nakahira, Kiichi
- Rogers, Angela J.
- Gazourian, Lee
- Youn, Sojung
- Osorio, Juan C.
- Zhao, Yang
- Christie, Jason D.
- Meyer, Nuala J.
- Causland, Finnian R. Mc.
- Waikar, Sushrut S.
- Waxman, Aaron B.
- Chung, Raymond T.
- Bueno, Raphael
- Fredenburgh, Laura E.
- Baron, Rebecca M.
- Christiani, David C.
- Hunninghake, Gary M.
- Choi, Augustine M. K.
- Venue
- PLoS Medicine
- Publisher
- Public Library of Science (PLoS)
- Published
- 2013-12-31
- Volume
- 10
- Issue
- 12
- Pages
- e1001577
- ISSN
- 1549-1277 (ISSN-L)
- 1549-1676
- PMC
- PMC3876981
- OpenAlex
- W2137274600
- Cited by
- 445
- References
- 44
- Citations by year
- 2026: 24 · 2025: 24 · 2024: 28 · 2023: 29 · 2022: 51 · 2021: 45 · 2020: 45 · 2019: 44 · 2018: 40 · 2017: 45 · 2016: 29 · 2015: 29 · 2014: 11
- FWCI
- 16.79
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS Medicine (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- Satellite Healthcare
- National Institutes of Health (HL087115, P01 HL108801, R01 HL079904, and R01 HL112747, ES-00002)
- National Heart, Lung, and Blood Institute (R01HL055330, T32HL007680, R01HL079904, K08HL092222, P01HL108801, T32 HL7118, R01HL060234, R01HL112747, R01HL111024, R01HL086919, R01HL060710, R01HL087115, R01HL091957, T32HL007633, T32HL007118)
- National Institute of General Medical Sciences (K08GM083207)
- National Institute of Environmental Health Sciences (P30ES000002, ES 00002)
- Topics
- Health Sciences › Medicine › Epidemiology › Sepsis Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Immunology and Microbiology › Immunology › Inflammation biomarkers and pathways
- Keywords
- mitochondrial DNA, circulating biomarkers, ICU mortality, risk prediction, acute respiratory distress syndrome, sepsis, medical intensive care, plasma biomarkers, inflammation
- MeSH terms
- Aged, DNA, Mitochondrial, Female, Humans, Intensive Care Units, Male, Middle Aged, Prospective Studies, Biomarkers, Hospital Mortality
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