Department of Biomedical Engineering, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
Department of Biomedical Engineering, Marquette University, Milwaukee, WI 53223, USA.
Function (Oxf). 2023 Jul 25;4(5):zqad038. doi: 10.1093/function/zqad038. eCollection 2023.
Integrated computational modeling provides a mechanistic and quantitative framework to characterize alterations in mitochondrial respiration and bioenergetics in response to different metabolic substrates . These alterations play critical roles in the pathogenesis of diseases affecting metabolically active organs such as heart and kidney. Therefore, the present study aimed to develop and validate thermodynamically constrained integrated computational models of mitochondrial respiration and bioenergetics in the heart and kidney cortex and outer medulla (OM). The models incorporated the kinetics of major biochemical reactions and transport processes as well as regulatory mechanisms in the mitochondria of these tissues. Intrinsic model parameters such as Michaelis-Menten constants were fixed at previously estimated values, while extrinsic model parameters such as maximal reaction and transport velocities were estimated separately for each tissue. This was achieved by fitting the model solutions to our recently published respirometry data measured in isolated rat heart and kidney cortex and OM mitochondria utilizing various NADH- and FADH-linked metabolic substrates. The models were validated by predicting additional respirometry and bioenergetics data, which were not used for estimating the extrinsic model parameters. The models were able to predict tissue-specific and substrate-dependent mitochondrial emergent metabolic system properties such as redox states, enzyme and transporter fluxes, metabolite concentrations, membrane potential, and respiratory control index under diverse physiological and pathological conditions. The models were also able to quantitatively characterize differential regulations of NADH- and FADH-linked metabolic pathways, which contribute differently toward regulations of oxidative phosphorylation and ATP synthesis in the heart and kidney cortex and OM mitochondria.
整合计算模型为研究不同代谢底物作用下线粒体呼吸和生物能量变化的机制和定量框架提供了支持。这些变化在影响代谢活跃器官（如心脏和肾脏）的疾病发病机制中起着关键作用。因此，本研究旨在开发和验证心脏和肾脏皮质和外髓质（OM）的线粒体呼吸和生物能量学的热力学约束整合计算模型。该模型纳入了这些组织中线粒体的主要生化反应和运输过程的动力学以及调节机制。内在模型参数（如米氏常数）固定在之前估计的值，而外在模型参数（如最大反应和运输速度）则分别针对每种组织进行估计。通过将模型解拟合到我们最近发表的使用各种 NADH 和 FADH 连接代谢底物测量的离体大鼠心脏和肾脏皮质和 OM 线粒体的呼吸测定数据来实现这一点。通过预测未用于估计外在模型参数的额外呼吸测定和生物能量学数据来验证模型。模型能够预测组织特异性和底物依赖性的线粒体新兴代谢系统特性，例如氧化还原状态、酶和转运体通量、代谢物浓度、膜电位和呼吸控制指数，在各种生理和病理条件下。模型还能够定量描述 NADH 和 FADH 连接代谢途径的差异调节，这些途径对心脏和肾脏皮质和 OM 线粒体氧化磷酸化和 ATP 合成的调节有不同的贡献。
