Franco Rafael, Serrano-Marín Joan
CiberNed, Network Center for Neurodegenerative Diseases, National Spanish Health Institute Carlos III, 28029 Madrid, Spain.
Molecular Neurobiology Laboratory, Department de Bioquímica i Biomedicina Molecular, Universitat de Barcelona, 08028 Barcelona, Spain.
Biomedicines. 2022 May 22;10(5):1199. doi: 10.3390/biomedicines10051199.
The Krebs cycle in cells that contain mitochondria is necessary for both energy production and anabolic processes. In given cell/condition, the Krebs cycle is dynamic but remains at a steady state. In this article, we first aimed at comparing the properties of a closed cycle versus the same metabolism in a linear array. The main finding is that, unlike a linear metabolism, the closed cycle can reach a steady state (SS) regardless of the nature and magnitude of the disturbance. When the cycle is modeled with input and output reactions, the "open" cycle is robust and reaches a steady state but with exceptions that lead to sustained accumulation of intermediate metabolites, i.e., conditions at which no SS can be achieved. The modeling of the cycle in cancer, trying to obtain marked reductions in flux, shows that these reductions are limited and therefore the Warburg effect is moderate at most. In general, our results of modeling the cycle in different conditions and looking for the achievement, or not, of SS, suggest that the cycle may have a regulation, not yet discovered, to go from an open cycle to a closed one. Said regulation could allow for reaching the steady state, thus avoiding the unwanted effects derived from the aberrant accumulation of metabolites in the mitochondria. The information in this paper might be useful to evaluate metabolism-modifying medicines.
在含有线粒体的细胞中，三羧酸循环对于能量产生和合成代谢过程均必不可少。在特定的细胞/条件下，三羧酸循环是动态的，但会保持在稳定状态。在本文中，我们首先旨在比较封闭循环与线性排列的相同代谢过程的特性。主要发现是，与线性代谢不同，无论干扰的性质和大小如何，封闭循环都能达到稳定状态（SS）。当用输入和输出反应对循环进行建模时，“开放”循环是稳健的并能达到稳定状态，但存在导致中间代谢产物持续积累的例外情况，即无法达到稳定状态的条件。对癌症中的循环进行建模，试图显著降低通量，结果表明这些降低是有限的，因此瓦伯格效应至多是中等程度的。总体而言，我们在不同条件下对循环进行建模并寻找是否达到稳定状态的结果表明，循环可能存在尚未被发现的调节机制，使其从开放循环转变为封闭循环。所述调节机制可以实现达到稳定状态，从而避免线粒体中代谢产物异常积累所产生的不良影响。本文中的信息可能有助于评估代谢调节药物。
