线粒体 DNA 丰度和循环代谢组学分析：英国生物库的多变量调整和孟德尔随机分析。

IF 3.9 3区生物学 Q2 CELL BIOLOGY

Mitochondrion Pub Date : 2024-11-24 DOI:10.1016/j.mito.2024.101991

Jiao Luo , Saskia le Cessie , Ko Willems van Dijk , Sara Hägg , Felix Grassmann , Diana van Heemst , Raymond Noordam

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引用次数: 0

摘要

背景：白细胞线粒体DNA（mtDNA）丰度低与动脉粥样硬化性心血管疾病的风险较高有关，但其机制尚不清楚。我们的目的是通过横断面研究和遗传学研究，调查低 mtDNA 丰度是否与代谢组学特征较差有关，并以此作为潜在的中间表型：在英国生物库（UK Biobank）的 61186 名无血缘关系的欧洲参与者中，我们进行了多变量调整线性回归分析，以研究 mtDNA 丰度与 168 种基于核磁共振（NMR）的循环代谢组测量指标和九种代谢组主成分（PC）之间的关联，这些主成分共涵盖了单个代谢组测量指标总变异的 91.5%。随后，我们进行了孟德尔随机化（MR），以近似确定mtDNA丰度对单个代谢组测量值及其代谢组主成分的因果效应：经多重检验校正后，mtDNA丰度低与130个代谢组相关，主要是一些氨基酸浓度较低，脂质、脂蛋白和脂肪酸浓度较高；此外，mtDNA丰度与9个代谢组PC中的7个相关。利用 MR，遗传预测的低 mtDNA 丰度与较低的乳酸（标准化贝塔值和 95% 置信区间：-0.17；-0.26，-0.08）、较高的醋酸（0.15；0.07，0.23）和不饱和度（0.14；0.08，0.20）相关。同样，基因预测的低 mtDNA 丰度与较低的代谢组 PC2（与较低的脂类和脂肪酸浓度有关）和较高的代谢组 PC9（与较低的糖酵解相关代谢物浓度有关）相关：结论：mtDNA丰度低与代谢组紊乱有关，特别是反映了一种促动脉粥样硬化的代谢组特征，这有可能将mtDNA丰度低与动脉粥样硬化风险升高联系起来。

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Mitochondrial DNA abundance and circulating metabolomic profiling: Multivariable-adjusted and Mendelian randomization analyses in UK Biobank

Background

Low leukocyte mitochondrial DNA (mtDNA) abundance has been associated with a higher risk of atherosclerotic cardiovascular disease, but through unclear mechanisms. We aimed to investigate whether low mtDNA abundance is associated with worse metabolomic profiling, as being potential intermediate phenotypes, using cross-sectional and genetic studies.

Methods

Among 61,186 unrelated European participants from UK Biobank, we performed multivariable-adjusted linear regression analyses to examine the associations between mtDNA abundance and 168 NMR-based circulating metabolomic measures and nine metabolomic principal components (PCs) that collectively covered 91.5% of the total variation of individual metabolomic measures. Subsequently, we conducted Mendelian randomization (MR) to approximate the causal effects of mtDNA abundance on the individual metabolomic measures and their metabolomic PCs.

Results

After correction for multiple testing, low mtDNA abundance was associated with 130 metabolomic measures, predominantly lower concentrations of some amino acids and higher concentrations of lipids, lipoproteins and fatty acids; moreover, mtDNA abundance was associated with seven out of the nine metabolomic PCs. Using MR, genetically-predicted low mtDNA abundance was associated with lower lactate (standardized beta and 95% confidence interval: −0.17; −0.26, −0.08), and higher acetate (0.15; 0.07,0.23), and unsaturation degree (0.14; 0.08,0.20). Similarly, genetically-predicted low mtDNA abundance was associated with lower metabolomic PC2 (related to lower concentrations of lipids and fatty acids), and higher metabolomic PC9 (related to lower concentrations of glycolysis-related metabolites).

Conclusion

Low mtDNA abundance is associated with metabolomic perturbations, particularly reflecting a pro-atherogenic metabolomic profile, which potentially could link low mtDNA abundance to higher atherosclerosis risk.

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来源期刊

Mitochondrion 生物-细胞生物学

CiteScore

9.40

自引率

4.50%

发文量

审稿时长

13.6 weeks

期刊介绍： Mitochondrion is a definitive, high profile, peer-reviewed international research journal. The scope of Mitochondrion is broad, reporting on basic science of mitochondria from all organisms and from basic research to pathology and clinical aspects of mitochondrial diseases. The journal welcomes original contributions from investigators working in diverse sub-disciplines such as evolution, biophysics, biochemistry, molecular and cell biology, genetics, pharmacology, toxicology, forensic science, programmed cell death, aging, cancer and clinical features of mitochondrial diseases.