Laboratory of Paediatrics, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands.
Section of Metabolic Diseases, Beatrix Children's Hospital, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands.
BMC Biol. 2023 Sep 4;21(1):184. doi: 10.1186/s12915-023-01652-9.
Monogenetic inborn errors of metabolism cause a wide phenotypic heterogeneity that may even differ between family members carrying the same genetic variant. Computational modelling of metabolic networks may identify putative sources of this inter-patient heterogeneity. Here, we mainly focus on medium-chain acyl-CoA dehydrogenase deficiency (MCADD), the most common inborn error of the mitochondrial fatty acid oxidation (mFAO). It is an enigma why some MCADD patients-if untreated-are at risk to develop severe metabolic decompensations, whereas others remain asymptomatic throughout life. We hypothesised that an ability to maintain an increased free mitochondrial CoA (CoASH) and pathway flux might distinguish asymptomatic from symptomatic patients.
We built and experimentally validated, for the first time, a kinetic model of the human liver mFAO. Metabolites were partitioned according to their water solubility between the bulk aqueous matrix and the inner membrane. Enzymes are also either membrane-bound or in the matrix. This metabolite partitioning is a novel model attribute and improved predictions. MCADD substantially reduced pathway flux and CoASH, the latter due to the sequestration of CoA as medium-chain acyl-CoA esters. Analysis of urine from MCADD patients obtained during a metabolic decompensation showed an accumulation of medium- and short-chain acylcarnitines, just like the acyl-CoA pool in the MCADD model. The model suggested some rescues that increased flux and CoASH, notably increasing short-chain acyl-CoA dehydrogenase (SCAD) levels. Proteome analysis of MCADD patient-derived fibroblasts indeed revealed elevated levels of SCAD in a patient with a clinically asymptomatic state. This is a rescue for MCADD that has not been explored before. Personalised models based on these proteomics data confirmed an increased pathway flux and CoASH in the model of an asymptomatic patient compared to those of symptomatic MCADD patients.
We present a detailed, validated kinetic model of mFAO in human liver, with solubility-dependent metabolite partitioning. Personalised modelling of individual patients provides a novel explanation for phenotypic heterogeneity among MCADD patients. Further development of personalised metabolic models is a promising direction to improve individualised risk assessment, management and monitoring for inborn errors of metabolism.
单基因遗传代谢缺陷导致广泛的表型异质性，即使在携带相同遗传变异的家庭成员之间也可能存在差异。代谢网络的计算建模可能会识别出这种患者间异质性的潜在来源。在这里，我们主要关注中链酰基辅酶 A 脱氢酶缺乏症（MCADD），这是线粒体脂肪酸氧化（mFAO）中最常见的遗传缺陷。令人费解的是，为什么有些未经治疗的 MCADD 患者会有发生严重代谢失代偿的风险，而另一些患者则终生无症状。我们假设能够维持增加的游离线粒体 CoA（CoASH）和途径通量可以将无症状患者与有症状患者区分开来。
我们首次构建并实验验证了人类肝脏 mFAO 的动力学模型。根据其水溶性，将代谢物分配到细胞质基质和内膜之间。酶要么是膜结合的，要么是在基质中的。这种代谢物分配是一个新的模型属性，并提高了预测的准确性。MCADD 大大降低了途径通量和 CoASH，后者是由于 CoA 作为中链酰基辅酶 A 酯而被隔离。对 MCADD 患者在代谢失代偿期间获得的尿液进行分析表明，中链和短链酰基肉碱积累，就像 MCADD 模型中的酰基辅酶 A 池一样。该模型提出了一些挽救措施，增加了通量和 CoASH，特别是增加了短链酰基辅酶 A 脱氢酶（SCAD）的水平。MCADD 患者来源成纤维细胞的蛋白质组分析确实揭示了处于临床无症状状态的患者中 SCAD 水平升高。这是对 MCADD 的一种挽救，以前尚未被探索过。基于这些蛋白质组学数据的个性化模型证实，与有症状的 MCADD 患者相比，无症状患者模型中的途径通量和 CoASH 增加。
我们提出了一种详细的、经过验证的人类肝脏 mFAO 动力学模型，具有依赖于溶解度的代谢物分配。对个体患者进行个性化建模为 MCADD 患者表型异质性提供了新的解释。进一步开发个性化代谢模型是改善代谢缺陷个体风险评估、管理和监测的有前途的方向。
