Date Published: July 13, 2017
Publisher: Public Library of Science
Author(s): Judita Knez, Vannina G. Marrachelli, Nicholas Cauwenberghs, Ellen Winckelmans, Zhenyu Zhang, Lutgarde Thijs, Jana Brguljan-Hitij, Michelle Plusquin, Christian Delles, Daniel Monleon, Josep Redón, Jan A. Staessen, Tim S. Nawrot, Tatiana Kuznetsova, David C. Samuels.
Mitochondrial DNA (mtDNA) content might undergo significant changes caused by metabolic derangements, oxidative stress and inflammation that lead to development and progression of cardiovascular diseases. We, therefore, investigated in a general population the association of peripheral blood mtDNA content with circulating metabolites and inflammatory markers. We examined 310 subjects (50.6% women; mean age, 53.3 years) randomly selected from a Flemish population. Relative mtDNA content was measured by quantitative real-time PCR in peripheral blood cells. Peak circulating metabolites were quantified using nuclear magnetic resonance spectroscopy. The level of inflammation was assessed via established inflammatory markers. Using Partial Least Squares analysis, we constructed 3 latent factors from the 44 measured metabolites that explained 62.5% and 8.5% of the variance in the contributing metabolites and the mtDNA content, respectively. With adjustments applied, mtDNA content was positively associated with the first latent factor (P = 0.002). We identified 6 metabolites with a major impact on the construction of this latent factor including HDL3 apolipoproteins, tyrosine, fatty acid with αCH2, creatinine, β-glucose and valine. We summarized them into a single composite metabolite score. We observed a negative association between the composite metabolic score and mtDNA content (P = 0.001). We also found that mtDNA content was inversely associated with inflammatory markers including hs-CRP, hs-IL6, white blood cell and neutrophil counts as well as neutrophil-to-lymphocyte ratio (P≤0.0024). We demonstrated that in a general population relative peripheral blood mtDNA content was associated with circulating metabolites indicative of perturbed lipid metabolism and with inflammatory biomarkers.
Atherosclerotic vascular disease is the leading cause of morbidity and mortality . Development and progression of atherosclerosis in vascular wall is associated with complex processes of metabolic derangements, oxidative stress and inflammation . Several lines of evidence imply that mitochondrial DNA (mtDNA) damage and subsequent organelle dysfunction might be the link between these processes [3–5].
The main finding of the present study was that in a general population lower peripheral blood mtDNA content was associated with higher levels of circulating metabolites indicative of disturbed lipid metabolism. Moreover, participants with higher levels of “classical” inflammatory markers such as hs-CRP, hs-IL-6 and neutrophil-to-lymphocyte ratio, had lower blood mtDNA content.
The present cross-sectional study demonstrated that peripheral blood mtDNA content in a general population is associated with a profile of circulating metabolites indicative of perturbed lipid metabolism, oxidative stress and inflammation. Further studies are necessary to clarify the molecular mechanisms governing this association and confirm its potential clinical usefulness.