3-Hydroxybutyrate, a metabolite in sustaining neuronal cell vitality: a mendelian randomization and in vitro experimentation.

IF 3.9 2区医学 Q2 NUTRITION & DIETETICS

Nutrition & Metabolism Pub Date : 2025-07-11 DOI:10.1186/s12986-025-00960-x

Xiaoling Hu, Yu Lin, Kaiwen Huang, HuiLin Xu, Changmei Huang Fu, Jiayin Ou, Xiude Fan, Zhe Li, Jiansong Fang, Shuhuan Fang

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引用次数: 0

Abstract

Background: Recent research has implicated mitochondrial DNA copy number (mtDNA-CN) and Tau protein levels in the blood as potential biomarkers for early Alzheimer's disease (AD) risk assessment, correlating with metabolite profiles. However, intermediary metabolites mediating these associations remain elusive.

Methods: Employing a two-sample and a mediation Mendelian randomization (MR) analysis of the IEU OpenGWAS database, involving 383,476 participants from a genome-wide association study (GWAS) and an exome-wide association study (ExWAS), we identified intermediary metabolites linking mtDNA-CN and Tau.Meanwhile, the effects of mediating metabolites on HT22 cell viability and its mitochondrial morphology were also assessed in conjunction with in vitro experiments.

Results: Our study revealed an association of mtDNA-CN on Tau (OR = 3.102, 95% CI: 1.016-9.472, P = 0.047), as well as on other 31 metabolites such as 3-Hydroxybutyrate (3HB), Docosahexaenoic acid (DHA), Acetate, Albumin, Apolipoprotein A-I (APOA1), and so on. Notably, 3HB was further implicated in a relationship with Tau (OR = 6.030, 95% CI: 1.054-34.491, P = 0.043), acting as a mediator between mtDNA-CN and Tau. In vitro experiments demonstrated that 3HB positively sustained HT22 cell viability by MTT assay and mitigated mitochondrial swelling under low glucose conditions, as observed via HIS-SIM. In Western blot (WB) and quantitative real-time PCR (qPCR) assays, phosphorylation levels of Tau at serine 262 (p-Tau262) and serine 396 (p-Tau396) were tended to decline following 3HB intervention. Additionally, a positive correlation was identified between 3HB concentration and mtDNA-CN.

Conclusions: These findings underscore the potential of 3HB as a biomarker and mediator in early AD risk assessment. Moreover, 3HB's ability to enhance cell viability, maintain mitochondrial morphology, decrease phosphorylated Tau protein expression and increase mtDNA-CN under stressful conditions, suggesting its therapeutic potential in improving the imbalance of energy metabolism in the AD brain.

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3-羟基丁酸，维持神经细胞活力的代谢物：孟德尔随机化和体外实验。

背景：最近的研究表明，血液中的线粒体DNA拷贝数（mtDNA-CN）和Tau蛋白水平与代谢物谱相关，是早期阿尔茨海默病（AD）风险评估的潜在生物标志物。然而，介导这些关联的中间代谢物仍然难以捉摸。方法：采用双样本和中介孟德尔随机化（MR）分析IEU OpenGWAS数据库，包括383,476名来自全基因组关联研究（GWAS）和外显子组关联研究（ExWAS）的参与者，我们确定了连接mtDNA-CN和Tau的中间代谢物。同时，结合体外实验，评估了介导代谢物对HT22细胞活力和线粒体形态的影响。结果：mtDNA-CN与Tau蛋白（OR = 3.102, 95% CI: 1.016-9.472, P = 0.047）、3-羟基丁酸（3HB）、二十二碳六烯酸（DHA）、醋酸酯、白蛋白、载脂蛋白A-I （APOA1）等31种代谢物相关。值得注意的是，3HB进一步与Tau相关（OR = 6.030, 95% CI: 1.054-34.491, P = 0.043），作为mtDNA-CN和Tau之间的中介。体外实验表明，通过MTT法，3HB积极维持HT22细胞活力，并减轻低糖条件下线粒体肿胀，通过HIS-SIM观察到。Western blot （WB）和实时荧光定量PCR （qPCR）检测显示，3HB干预后，Tau蛋白丝氨酸262 （p-Tau262）和丝氨酸396 （p-Tau396）磷酸化水平有下降趋势。此外，3HB浓度与mtDNA-CN呈正相关。结论：这些发现强调了3HB作为早期AD风险评估的生物标志物和中介的潜力。此外，在应激条件下，3HB具有增强细胞活力、维持线粒体形态、降低磷酸化Tau蛋白表达和增加mtDNA-CN的能力，表明其在改善AD大脑能量代谢失衡方面具有治疗潜力。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Nutrition & Metabolism 医学-营养学

CiteScore

8.40

自引率

0.00%

发文量

审稿时长

4-8 weeks

期刊介绍： Nutrition & Metabolism publishes studies with a clear focus on nutrition and metabolism with applications ranging from nutrition needs, exercise physiology, clinical and population studies, as well as the underlying mechanisms in these aspects. The areas of interest for Nutrition & Metabolism encompass studies in molecular nutrition in the context of obesity, diabetes, lipedemias, metabolic syndrome and exercise physiology. Manuscripts related to molecular, cellular and human metabolism, nutrient sensing and nutrient–gene interactions are also in interest, as are submissions that have employed new and innovative strategies like metabolomics/lipidomics or other omic-based biomarkers to predict nutritional status and metabolic diseases. Key areas we wish to encourage submissions from include: -how diet and specific nutrients interact with genes, proteins or metabolites to influence metabolic phenotypes and disease outcomes; -the role of epigenetic factors and the microbiome in the pathogenesis of metabolic diseases and their influence on metabolic responses to diet and food components; -how diet and other environmental factors affect epigenetics and microbiota; the extent to which genetic and nongenetic factors modify personal metabolic responses to diet and food compositions and the mechanisms involved; -how specific biologic networks and nutrient sensing mechanisms attribute to metabolic variability.