ccf-mtDNA Levels Research Articles

Cell-free mitochondrial DNA in progressive multiple sclerosis

Recent studies have linked cell-free mitochondrial DNA (ccf-mtDNA) to neurodegeneration in both Alzheimer's and Parkinson's disease, raising the possibility that the same phenomenon could be seen in other diseases which manifest a neurodegenerative component. Here, we assessed the role of circulating cell-free mitochondrial DNA (ccf-mtDNA) in end-stage progressive multiple sclerosis (PMS), where neurodegeneration is evident, contrasting both ventricular cerebral spinal fluid ccf-mtDNA abundance and integrity between PMS cases and controls, and correlating ccf-mtDNA levels to known protein markers of neurodegeneration and PMS. Our data indicate that reduced ccf-mtDNA is a component of PMS, concluding that it may indeed be a hallmark of broader neurodegeneration.

Circulating cell-free mitochondrial DNA, but not leukocyte mitochondrial DNA copy number, is elevated in major depressive disorder

Major depressive disorder (MDD) has been linked to mitochondrial defects, which could manifest in mitochondrial DNA (mtDNA) polymorphisms or mutations. Additionally, copy number of mtDNA (mtDNA-cn) can be quantified in peripheral blood mononuclear cells (PBMC)s, indirectly reflecting cellular energetics, or in the circulating cell-free mtDNA (ccf-mtDNA) levels, which may reflect a fraction of the mitochondrial genome released during cellular stress. Few studies have examined ccf-mtDNA in MDD, and no studies have tested its relationship with intracellular mtDNA-cn or with antidepressant treatment response. Here, mtDNA levels were quantified in parallel from: (i) PBMCs and (ii) cell-free plasma of 50 unmedicated MDD subjects and 55 controls, in parallel with PBMC telomere length (TL) and antioxidant enzyme glutathione peroxidase (GpX) activity. MtDNA measures were repeated in 19 MDD subjects after 8 weeks of open-label SSRI treatment. In analyses adjusted for age, sex, BMI, and smoking, MDD subjects had significantly elevated levels of ccf-mtDNA (F = 20.6, p = 0.00002). PBMC mtDNA-cn did not differ between groups (p > 0.4). In preliminary analyses, we found that changes in ccf-mtDNA with SSRI treatment differed between SSRI responders and non-responders (F = 6.47, p = 0.02), with the non-responders showing an increase in ccf-mtDNA and responders not changing. Baseline ccf-mtDNA was positively correlated with GpX (r = 0.32, p = 0.001), and PBMC mtDNA correlated positively with PBMC TL (r = 0.38, p = 0.0001). These data suggest that plasma ccf-mtDNA and PBMC mtDNA-cn reflect different cellular processes and that the former may be more reflective of certain aspects of MDD pathophysiology and of the response to SSRI antidepressants.

P 164 - Circulating mtDNA levels as an early marker for metabolic syndrome

Chronic diseases, infection and physical activity are conditions related with metabolic or oxidative stress and the releasing of mitochondria to circulation by cells. This might be due to apoptosis or transference of mitochondria from one cell to another, either as survival or as tissue repair process. Circulating levels of cell-free mitochondrial DNA (ccf-mtDNA), although controversial, have been used for cancer and sepsis diagnose. The objective of this study was to investigate the relationship between ccf-mtDNA and metabolic syndrome. In this sense, after IRB approval, healthy subjects (n=32) and adults with diabetes (n=6) were invited to participate. Body mass index (BMI) was calculated and fasting glucose measured as biomarker of metabolic syndrome. In addition, DNA was extracted from serum and real time PCR used to detect ccf-mtDNA and both parameters were compared. Our data showed that ccf-mtDNA values ranged from 10 to 100 ng/ml in subjects with normal BMI while there were no detectable levels of ccf-mtDNA in samples from overweight subjects and diabetic patients. Glucose levels did not show differences independently of their BMI, but there was an inverse relationship between ccf-mtDNA and BMI. In conclusion, our results suggest that ccf-mtDNA might represent an early biomarker to identify people with metabolic syndrome or at risk for future develpment of diabetes.

Plasma mitochondrial DNA at admission can predict the outcome of acute trauma patients admitted to ICU

ObjectivesWe assessed whether at admission plasma circulating cell free mitochondrial DNA (ccf-mtDNA) is related to injury severity and can predict morbidity and mortality in acute trauma patients.Patients and methodsPatients were evaluated at Emergency Department (ED) using Injury Severity Scale (ISS), but only patients required ICU admission were studied (Group B). At ED arrival, blood samples were obtained for quantitative real-time PCR estimation of plasma level of ccf-mtDNA. Study outcome was the correlation between morbidity and mortality and at admission plasma ccf-mtDNA level and its predictability for morbidity and mortality. Ten healthy volunteers gave blood samples as control group (Group B).ResultsTwenty-seven patients passed smooth ICU stay and were discharged alive (Group B1), while 34 patients developed additional morbidities (Group B2) and 11 patients (18%) of Group A2 died. Mean estimated plasma ccf-mtDNA levels were significantly higher in Group B than in Group A, but patients of Group B1 had significantly lower ccf-mtDNA levels than patients of Group B2. Patients developed adult respiratory distress syndrome (ARDS) had significantly higher ccf-mtDNA levels than patients developed sepsis or acute myocardial infarction (AMI) with significantly higher levels in patients developed sepsis. Estimated plasma ccf-mtDNA levels at time of admission showed positive significant correlation with morbidity rate. Odds ratio (OR) for relative risk for development of additional morbidities in patients who had a high plasma ccf-mtDNA level was 26.35. At admission plasma ccf-mtDNA levels in survivors were significantly lower than in non-survivors, and OR was 4.0806. High plasma ccf-mtDNA showed high sensitivity as predictor for ICU mortality.ConclusionHigh at ED admission plasma ccf-mtDNA levels could predict development of additional morbidities during ICU stay of acute trauma patients and showed high sensitivity for prediction of their survival. Very high plasma ccf-mtDNA levels could predict patients liable to develop ARDS.

Circulating cell-free mitochondrial deoxyribonucleic acid is increased in coronary heart disease patients with diabetes mellitus.

Circulating cell-free mitochondrial deoxyribonucleic acid (ccf-mtDNA) is presumably derived from injured tissues or cells in the body and has been suggested to be potential biomarker in several diseases. The present study explored whether mtDNA could be used as a biomarker to evaluate disease in coronary heart disease (CHD) patients with or without diabetes mellitus (DM). A total of 50 CHD patients with type2 diabetes, 50 CHD patients without type2 diabetes, and 50 age- and sex-matched patients without CHD and DM (non-CHD-DM) were recruited. Ccf-mtDNA levels were assessed by measuring the nicotinamide adenine dinucleotide dehydrogenase1 gene using quantitative real-time polymerase chain reaction. Receiver operating characteristic curve analysis of plasma mtDNA in CHD with or without DM was also determined. Multivariate logistic regression analyses were carried out to determine the correlation between the mtDNA levels and traditional CHD risk factors. The plasma ccf-mtDNA levels were significantly elevated in CHD patients with DM compared with those without and non-CHD-DM. The area under the receiver operating characteristic curves of mtDNA in CHD patients with DM vs non-CHD-DM was 0.907%. Correlation analyses of the mtDNA levels and traditional CHD risk factors showed that the mtDNA levels were significantly correlated with fasting blood glucose in CHD patients with DM. Ccf-mtDNA levels can be used as a biomarker in CHD patients with DM.

Circulating Cell Free Mitochondrial DNA is a Biomarker in the Development of Coronary Heart Disease in the Patients with Type 2 Diabetes.

Circulating cell-free mtDNA (ccf-mtDNA) is presumably derived from injured tissue or cells in the body and has been suggested to be a potential biomarker in several diseases. In the present study, we investigated whether ccf-mtDNA levels could serve as a biomarker of diabetic patients without Coronary Heart Disease (CHD) and correlate with their incidence to develop CHD. Ccf-mtDNA levels in plasma and the traditional CHD risk factors were determined in 50 type 2 diabetes (DM) with CHD and 50 DM without CHD patients and 50 age- and sex-matched healthy controls. MtDNA levels were assessed by measuring the NADH dehydrogenase 1 gene using quantitative real-time PCR. ROC curve analyses of plasma mtDNA in DM with or without CHD were also determined. Multivariate logistic regression analyses were conducted to determine the correlation between the mtDNA levels and traditional CHD risk factors. The plasma ccf-mtDNA levels and CRP were significantly elevated in DM compared with healthy controls, and a consistent increase of mtDNA in diabetes with CHD compared to those without CHD. The area under the ROC curves of mtDNA in DM patients versus DM patients with CHD and healthy controls was 0.843 and 0.898, respectively. Correlation analyses showed that the mtDNA levels were significantly correlated with that of C-reactive protein (CRP) in patients with CHD. Ccf-mtDNA was elevated in type 2 diabetes with CHD and correlated with CRP levels. Both may be considered a prognostic biomarker of CHD development.

Cell-free Circulating Mitochondrial DNA in the Serum: A Potential Non-invasive Biomarker for Ewing's Sarcoma

Altered levels of circulating cell-free mitochondrial DNA (ccf mtDNA) have been recently detected in several cancer types and have been proposed as a promising noninvasive diagnostic or prognostic biomarker. There has been no report regarding quantification of ccf mtDNA in patients with Ewing's sarcoma (EWS). Ccf mtDNA copy number in serum samples obtained from 25 patients with EWS as well as 20 age-matched individuals were detected by quantitative real-time PCR assays. A receiver operating characteristic (ROC) curve analysis was performed to evaluate the diagnostic applicability of serum ccf mtDNA as a noninvasive biomarker for discriminating between patients and healthy cohorts. The potential connection between ccf mtDNA levels and various clinicopathological factors of EWS was also determined. We found that levels of ccf mtDNA in the serum of EWS patients were significantly lower than in healthy controls. The receiver operating curve analysis demonstrated that using serum ccf mtDNA content as a molecular marker allowed distinguishing between EWS patients and healthy subjects with a sensitivity of 76.1 and a specificity of 68.4%. In addition, serum levels of ccf mtDNA were associated with the status of tumor metastasis. These results suggest that serum ccf mtDNA has the potential capacity as a novel and convenient noninvasive biomarker for molecular diagnosis of EWS. Scrutinizing quantitative changes of serum ccf mtDNA may provide valuable clues for better management of EWS patients.