Making power supply meet power demand in cardiac cells: how (exactly) mitochondria synthesize and export ATP to the cytoplasm at a rate matching its hydrolysis rate there

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Abstract

We have developed a thermodynamically constrained computational model of mitochondrial adenosine
triphosphate (ATP) production and concomitant reactive oxygen species (ROS) production. The model is
comprised of modules simulating the kinetics of: (1) transporters and exchangers of phosphate, adenine
nucleotides, and tricarboxylic acid (TCA) cycle intermediates, (2) the catalytic steps of the TCA cycle, by which substrates are oxidized to generate the reducing equivalents NADH and FADH2, (3) the donation of electrons to the electron transport chain (ETC) by these reducing equivalents and the subsequent redox transfer through the four complexes of the ETC, (4) the pumping of protons out of the matrix coupled to the ETC, which energetically finances the maintenance of an electrical potential across the inner mitochondrial membrane (IMM), (5) the transduction of membrane potential to synthesize ATP via the F0F1-ATPase, and (6) the generation of ROS by various complexes of the ETC. This model constitutes a synthesis of, and improvement upon, earlier versions of the component modules from this research group and is the first model (from this or any group) to describe, entirely explicitly, the detailed chain of events by which the rate of supply of ATP by mitochondria to cytoplasm is able to match its rate of loss there to energy-consuming processes (by hydrolysis). The model predicts that when hydrolysis demands are very high (e.g. during hard exercise), the flux through pyruvate dehydrogenase (PDH), the entry-point into the TCA cycle for pyruvate generated by glycolysis, becomes rate-limiting for ATP synthesis. The model predicts that under these circumstances the flux through PDH is increased by the action of PDH phosphatase, which is known to sense mitochondrial energetic status and upregulate PDH accordingly.

Description

Math Bio Seminar
Sept. 2, 2022
12:00-1:00pm MST/AZ
WXLR A309 and virtual via Zoom

Those joining remotely can use this link: https://asu.zoom.us/j/88150475011.

Speaker

Lydia M. Bilinsky
Postdoctoral Fellow, Beard Laboratory
Molecular and Integrative Physiology, Medical School
University of Michigan

Location
WXLR A309 and virtual via Zoom