Nutrition in Prevention and Therapy, Institute for Nutritional Sciences, University of Giessen, Wilhelmstr. 20, 35392, Giessen, Germany.
Institute for Neuroradiology, Goethe University Frankfurt, Schleusenweg 2-16, 60528, Frankfurt/Main, Germany.
Biol Sex Differ. 2018 Jul 25;9(1):34. doi: 10.1186/s13293-018-0193-7.
Alzheimer's disease (AD) is the most common form of dementia, and it affects more women than men. Mitochondrial dysfunction (MD) plays a key role in AD, and it is detectable at an early stage of the degenerative process in peripheral tissues, such as peripheral mononuclear blood cells (PBMCs). However, whether these changes are also reflected in cerebral energy metabolism and whether sex-specific differences in mitochondrial function occur are not clear. Therefore, we estimated the correlation between mitochondrial function in PBMCs and brain energy metabolites and examined sex-specific differences in healthy participants to elucidate these issues.
The current pilot study included 9 male and 15 female healthy adults (mean age 30.8 ± 7.1 years). Respiration and activity of mitochondrial respiratory complexes were measured using a Clarke-electrode (Oxygraph-2k system), and adenosine triphosphate (ATP) levels were determined using a bioluminescence-based assay in isolated PBMCs. Citrate synthase activity as a mitochondrial marker was measured using a photometric assay. Concentrations of brain energy metabolites were quantified in the same individuals using H-magnetic resonance spectroscopy (MRS).
We detected sex-associated differences in mitochondrial function. Mitochondrial complexes I, I+II, and IV and uncoupled respiration and electron transport system (ETS) capacity in PBMCs isolated from blood samples of females were significantly (p < 0.05; p < 0.01) higher compared to males. ATP levels in the PBMCs of female participants were approximately 10% higher compared to males. Citrate synthase (CS) activity, a marker of mitochondrial content, was significantly (p < 0.05) higher in females compared to males. Sex-associated differences were also found for brain metabolites. The N-acetylaspartate (NAA) concentration was significantly higher in female participants compared to males in targeted regions. This difference was observed in white matter (WM) and an area with a high percentage (> 50%) of gray matter (GM) (p < 0.05; p < 0.01). The effect sizes indicated a strong influence of sex on these parameters. Sex-associated differences were found in PBMCs and brain, but the determined parameters were not significantly correlated.
Our study revealed sex-associated differences in mitochondrial function in healthy participants. The underlying mechanisms must be elucidated in more detail, but our study suggests that mitochondrial function in PBMCs is a feasible surrogate marker to detect differences in mitochondrial function and energy metabolism in humans and it underscores the necessity of sex-specific approaches in therapies that target mitochondrial dysfunction.
阿尔茨海默病（AD）是最常见的痴呆症形式，女性患者多于男性。线粒体功能障碍（MD）在 AD 中起关键作用，并且在周围组织（如外周单核血细胞（PBMC））的退行性过程的早期即可检测到。然而，这些变化是否也反映在大脑能量代谢中，以及线粒体功能是否存在性别特异性差异尚不清楚。因此，我们评估了 PBMC 中的线粒体功能与脑能量代谢物之间的相关性，并在健康参与者中检查了线粒体功能的性别特异性差异，以阐明这些问题。
本初步研究纳入了 9 名男性和 15 名女性健康成年人（平均年龄 30.8±7.1 岁）。使用 Clarke 电极（Oxygraph-2k 系统）测量线粒体呼吸和呼吸复合物的活性，并使用基于生物发光的测定法在分离的 PBMC 中测定三磷酸腺苷（ATP）水平。使用比色法测量柠檬酸合酶活性作为线粒体标志物。使用 H-磁共振波谱（MRS）在同一个体中定量测定脑能量代谢物的浓度。
我们检测到了与性别相关的线粒体功能差异。与男性相比，来自女性血液样本的 PBMC 中的线粒体复合物 I、I+II 和 IV 以及解偶联呼吸和电子传递系统（ETS）容量显著（p<0.05；p<0.01）更高。女性参与者的 PBMC 中的 ATP 水平比男性高约 10%。与男性相比，女性的柠檬酸合酶（CS）活性（线粒体含量的标志物）显著（p<0.05）更高。在大脑代谢物方面也发现了与性别相关的差异。在靶向区域，女性参与者的 N-乙酰天冬氨酸（NAA）浓度明显高于男性。这种差异在白质（WM）和含有高比例（>50%）灰质（GM）的区域中观察到（p<0.05；p<0.01）。效应大小表明性别对这些参数有很大影响。在 PBMC 和大脑中都发现了与性别相关的差异，但确定的参数之间没有显著相关性。
我们的研究揭示了健康参与者中线粒体功能的性别差异。必须更详细地阐明潜在机制，但我们的研究表明，PBMC 中的线粒体功能是一种可行的替代标志物，可用于检测人类中线粒体功能和能量代谢的差异，并强调了针对线粒体功能障碍的治疗需要采用性别特异性方法。
