Modeling Mitochondrial Function in the Heart | Mitochondrial Biology Research

The Computational Systems Biology Laboratory's research specialty over the past several years has been to utilize mathematical and computational modeling, along with experimental measurements, at multiple levels of biological complexity (molecular, subcellular, cellular, tissue/organ) to inform, refine, and uncover a mechanistic understanding of a variety of biological systems. Much of this work is on the integrated physiology of solute transport and energy metabolism in tissue/organ systems, with a major focus on skeletal muscle, heart, and kidney cellular metabolism and energetics under normal and pathological conditions (e.g., hypoxia, ischemia, exercise, diabetes, and hypertension). These studies involved the development of multi-scale computational models encompassing molecular, subcellular, cellular, and tissue/organ processes and mechanisms, along with numerical methods and algorithms for model parameter optimization to experimental data, which is an important task in gaining mechanistic understandings of these biological systems. Such studies are crucial for quantitative understanding of the mechanisms of metabolic regulation in tissue/organ systems in vivo, including control of mitochondrial oxygen consumption (respiration), substrate and energy metabolism, and ATP homeostasis under different conditions. Such studies are also critical for understanding disease pathology and progression, specifically how subcellular events causing disturbances or malfunction at the cellular level are translated to affect whole-organ function causing disease (e.g., mutation in an ion channel causing heart disease).

Modeling Mitochondrial Function in the Heart 

The Computational Systems Biology Laboratory has recently focused on developing an integrated research program combining computational modeling and experimental measurements (collaborations with Drs. Daniel Beard, James Bassingthwaighte, Amadou Camara, David Stowe, Wai-Meng Kwok, and Zeljko Bosnjak) in the heart mitochondria and myocytes. The goal is to quantitatively characterize biophysical and biochemical mechanisms associated with mitochondrial handlings of cations (e.g., Ca2+) and reactive oxygen species (ROS—e.g., O2- ×, H2O2: the toxic byproducts of mitochondrial respiration that cause oxidative stress) in the heart mitochondria and myocytes, and to mechanistically investigate how Ca2+ and ROS interactions/crosstalk and dysregulations lead to mitochondrial dysfunction and mitochondria-mediated cardiac cellular injury/death under ischemia-reperfusion (IR) or hypoxia-reoxygenation (HR) conditions. Since mitochondria are responsible for the majority of energy (ATP) production in cardiac myocytes, their bioenergetic state is believed to be at the center of IR/HR injury phenotype and cardioprotection mechanisms. The goal of these integrated studies is to gain further understanding of the pathological conditions and to identify potential therapeutic targets that would help to minimize or reverse heart tissue injury following IR/HR.

In several recent research projects, the CSBL modeling group, in collaboration with Drs. Camara’s, Stowe’s, Bosnjak’s, and Bosnjak’s experimental groups, computationally characterized and investigated the specific effects and kinetic/molecular mechanisms of actions of volatile anesthetics (isoflurane) on proteins (channels, transporters, and enzymes) regulating mitochondrial and cellular functions (electrophysiology, bioenergetics, and Ca2+-ROS handlings) that lead to cardioprotection against IR/HR injury.

Mitochondrial Biology Research

In the past few years, the Computational Systems Biology Laboratory has established a wet lab for mitochondrial biology research and has expanded its collaborative efforts within MCW and other academic institutions in the USA and abroad. Specifically, the CSBL has identified applications of his experimental and computational modeling approaches for investigating the functioning of a variety of biological/physiological systems in health and diseases.

 

Mitochondrial Modeling Projects

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Renal Dysfunction and Salt-Sensitive Hypertension

Integrated experimental biology and computational modeling of renal cellular and mitochondrial metabolic pathways to quantitatively characterize and mechanistically investigate the role of metabolic dysfunction and oxidative stress (cell membrane NADPH oxidase and mitochondria ROS-ROS crosstalk) in renal dysfunction and salt-sensitive hypertension

Collaborators

Drs. Allen Cowley, Department of Physiology—Medical College of Wisconsin

Mingyu Liang, Department of Physiology—Medical College of Wisconsin

Lung Tissue Bioenergetics

Multi-scale computational modeling of lung tissue bioenergetics to quantitatively characterize and mechanistically investigate the metabolic basis of acute lung injury and acute respiratory distress syndrome, incorporating the critical roles of mitochondrial dysfunction and oxidative stress

Collaborators

Dr. Said Audi, Joint Department of Biomedical Engineering—Marquette University and the Medical College of Wisconsin

Gas Exchange in the Lungs

Mathematical modeling of gas exchange in the lungs involving a mixture of physiological and inert gases to investigate the effects of ventilation-perfusion inequality on gas exchange, second gas effects, and lungs respiratory function

Collaborators

Dr. Ben Korman, Anesthesiology—Royal Perth Hospital, Australia

Human Cell-Cycle Dysregulation in Disease

Integrated computational modeling and quantitative analysis of large-scale biochemical networks, protein-protein interaction networks, and gene regulatory networks to quantitatively characterize and mechanistically investigate the complex genotype-phenotype relationships and human cell cycle dysregulation in diverse disease pathologies, including human cytomegalovirus infection and cancer

Collaborators

Dr. Scott Terhune, Department of Microbiology and Immunology—Medical College of Wisconsin