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• Cortassa, S
• O’Rourke, B
• Winslow, RL.
• Aon, MA.
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• Cortassa, S
• O’Rourke, B
• Winslow, RL.
• Aon, MA.
• [+] on PubMed
• Cortassa, S
• O’Rourke, B
• Winslow, RL.
• Aon, MA.

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Int. J. Mol. Sci. 2009, 10(4), 1500-1513; doi:10.3390/ijms10041500

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Control and Regulation of Integrated Mitochondrial Function in Metabolic and Transport Networks

Sonia Cortassa ^1,* , Brian O’Rourke ¹ , Raimond L. Winslow ²  and Miguel A. Aon ¹

¹ Johns Hopkins University, School of Medicine, Division of Cardiology 720 Rutland Ave, 1059 Ross Bldg, Baltimore, MD 21205, USA ² Institute for Computational Medicine, 3400 N. Charles St. CSEB 315, Baltimore, MD 21218, USA

* Author to whom correspondence should be addressed.

Received: 21 February 2009; in revised form: 26 March 2009 / Accepted: 30 March 2009 / Published: 1 April 2009

(This article belongs to the Special Issue Molecular System Bioenergetics)

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Abstract: The pattern of flux and concentration control coefficients in an integrated mitochondrial energetics model is examined by applying a generalized matrix method of control analysis to calculate control coefficients, as well as response coefficients The computational model of Cortassa et al. encompasses oxidative phosphorylation, the TCA cycle, and Ca²⁺ dynamics. Control of ATP synthesis, TCA cycle, and ANT fluxes were found to be distributed among various mitochondrial processes. Control is shared by processes associated with ATP/ADP production and transport, as well as by Ca²⁺ dynamics. The calculation also analyzed the control of the concentrations of key regulatory ions and metabolites (Ca²⁺, NADH, ADP). The approach we have used demonstrates how properties of integrated systems may be understood through applications of computational modeling and control analysis.

Keywords: Mitochondrial computational model; mitochondrial energetics; excitation-contraction coupling; calcium dynamics; metabolic control analysis; distributed control; control by diffuse loops.

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