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

Abstract

Background Mitochondrial 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. Methods We 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. Results Circulating 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. Conclusion These results show that high circulating MT-DNA levels are a potential early indicator for poor COVID-19 outcomes. Funding Washington University Institute of Clinical Translational Sciences COVID-19 Research Program and Washington University Institute of Clinical Translational Sciences (ICTS) NIH grant UL1TR002345.

Implications of central carbon metabolism in SARS-CoV-2 replication and disease severity

“…Further delineation of the pathways indicated an inefficient mitochondrial metabolism as majority of the TCA cycle enzymes were downregulated in the infected cells. This was in line with the decreased mtDNA copy numbers in severe COVID-19 patients (Fig 5f) indicating a possible mitochondrial dysfunction as reported previously [13,[44][45][46].…”

Increased complement activation is a distinctive feature of severe SARS-CoV-2 infection

“…Analytes were measured in cell-free plasma collected from patients within the first 24 hours of emergency department presentation. In the WUSM COVID-19 and influenza cohorts, blood samples were collected in EDTA-containing vacutainers (BD Biosciences, San Jose, CA), transported on ice and spun down at 2,500 g (4,725 rpm) for 10 min at 4°C, after which they were stored at −80°C until further analysis (Mudd et al ., 2020; Scozzi et al ., 2021).…”

Group IIA Secreted Phospholipase A2 Plays a Central Role in the Pathobiology of COVID-19

“…Our data not only corroborates emerging evidence of elevated acetylcarnitine in COVID-19 patients, but also show that acetylcarnitine is an indicator of COVID-19 related mortality. Increases in mtDNA levels further support severe disease and mortality in COVID-19 31 . Together, our data indicate that defective fatty acid oxidation and mitochondrial dysfunction within vital organs may not only induce inflammatory damage 32,33 , but could underly sPLA 2 -IIA-related COVID-19 severity and mortality.…”

“…al. 31 Using genes for human cytochrome C (MT-CYB) and cytochrome C oxidase subunit III (MT- COX3), mtDNA was quantified in plasma samples from the same 34 patients (9 non-COVID-19, 8 mild, 7 severe, and 10 deceased COVID-19 patients) as in the sPLA2 activity assay utilizing an ABI 7900HT real-time PCR instrument in 384-well format. Synthetic oligonucleotide copies of the MT-CYB and MT-COX3 genomic sequences (gBlock Gene Fragments from Integrated DNA Technologies) were included to generate a standard curve at 10 5 , 10 4 , 10 3 , and 10 2 copies per µL.…”