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Role of cellular compartmentation in the metabolic response to stress: mechanistic insights from computational models.

Abstract：

:The mechanisms controlling ATP generation in the transition from normal resting conditions to either high work states or ischemia are poorly understood. ATP generation depends upon compartmentation between the mitochondria and cytosol of metabolic pathways and key energy transfer species that cannot be easily assessed experimentally. We developed a multicompartment mathematical model of cardiac metabolism to simulate the metabolic responses to ischemia and increased workload. The model is based on mass balances, transport, and metabolic processes in cardiac tissue, and has three distinct compartments (blood, cytosol, and mitochondria). In addition to distinguishing between cytosol and mitochondria, the model includes a cytosolic subcompartment for glycolytic metabolic channeling. The model simulations predict the rapid activation of glycogenolysis and lactate production at the onset of ischemia, and support the concept of localization of glycolysis to a cytosolic subcompartment. In addition, simulations show that mitochondrial NADH/NAD(+) is primarily determined by oxygen consumption during ischemia, while cytosolic NADH/NAD(+) and lactate production are largely a function of glycolytic flux during the initial phase, and is controlled by mitochondrial NADH/NAD(+) and the malate-aspartate shuttle during the steady state. Finally, the model predicts that metabolic activation with an abrupt increase in workload requires parallel activation of ATP hydrolysis, glycolysis, mitochondrial dehydrogenases, the electron transport chain, and ADP phosphorylation. Taken together, these studies demonstrate the importance of metabolic compartmentation in the regulation of cardiac energetics in response to acute stress, and they highlight the usefulness of computational models in this line of investigation.

journal_name

Ann N Y Acad Sci

journal_title

Annals of the New York Academy of Sciences

authors

Zhou L,Yu X,Cabrera ME,Stanley WC

doi

10.1196/annals.1380.012

subject

Has Abstract

pub_date

2006-10-01 00:00:00

pages

120-39

eissn

0077-8923

issn

1749-6632

pii

1080/1/120

journal_volume

1080

pub_type

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Role of cellular compartmentation in the metabolic response to stress: mechanistic insights from computational models.