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Multistationary and Oscillatory Modes of Free Radicals Generation by the Mitochondrial Respiratory Chain Revealed by a Bifurcation Analysis

Selivanov, VA and Cascante, M and Friedman, M and Schumaker, MF and Trucco, M and Votyakova, TV (2012) Multistationary and Oscillatory Modes of Free Radicals Generation by the Mitochondrial Respiratory Chain Revealed by a Bifurcation Analysis. PLoS Computational Biology, 8 (9). ISSN 1553-734X

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Abstract

The mitochondrial electron transport chain transforms energy satisfying cellular demand and generates reactive oxygen species (ROS) that act as metabolic signals or destructive factors. Therefore, knowledge of the possible modes and bifurcations of electron transport that affect ROS signaling provides insight into the interrelationship of mitochondrial respiration with cellular metabolism. Here, a bifurcation analysis of a sequence of the electron transport chain models of increasing complexity was used to analyze the contribution of individual components to the modes of respiratory chain behavior. Our algorithm constructed models as large systems of ordinary differential equations describing the time evolution of the distribution of redox states of the respiratory complexes. The most complete model of the respiratory chain and linked metabolic reactions predicted that condensed mitochondria produce more ROS at low succinate concentration and less ROS at high succinate levels than swelled mitochondria. This prediction was validated by measuring ROS production under various swelling conditions. A numerical bifurcation analysis revealed qualitatively different types of multistationary behavior and sustained oscillations in the parameter space near a region that was previously found to describe the behavior of isolated mitochondria. The oscillations in transmembrane potential and ROS generation, observed in living cells were reproduced in the model that includes interaction of respiratory complexes with the reactions of TCA cycle. Whereas multistationarity is an internal characteristic of the respiratory chain, the functional link of respiration with central metabolism creates oscillations, which can be understood as a means of auto-regulation of cell metabolism. © 2012 Selivanov et al.

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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Selivanov, VA
Cascante, M
Friedman, M
Schumaker, MF
Trucco, Mmnt@pitt.eduMNT
Votyakova, TV
Contributors:
ContributionContributors NameEmailPitt UsernameORCID
EditorBourne, Philip E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Date: 1 September 2012
Date Type: Publication
Journal or Publication Title: PLoS Computational Biology
Volume: 8
Number: 9
DOI or Unique Handle: 10.1371/journal.pcbi.1002700
Schools and Programs: School of Medicine > Pediatrics
Refereed: Yes
ISSN: 1553-734X
Other ID: NLM PMC3447950
PubMed Central ID: PMC3447950
PubMed ID: 23028295
Date Deposited: 19 Oct 2012 21:26
Last Modified: 04 Feb 2019 15:58
URI: http://d-scholarship.pitt.edu/id/eprint/16048

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