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Maintenance of Mitochondrial Oxygen Homeostasis by Cosubstrate Compensation

Kueh, Hao Yuan and Niethammer, Philipp and Mitchison, Timothy J. (2013) Maintenance of Mitochondrial Oxygen Homeostasis by Cosubstrate Compensation. Biophysical Journal, 104 (6). pp. 1338-1348. ISSN 0006-3495.

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Mitochondria maintain a constant rate of aerobic respiration over a wide range of oxygen levels. However, the control strategies underlying oxygen homeostasis are still unclear. Using mathematical modeling, we found that the mitochondrial electron transport chain (ETC) responds to oxygen level changes by undergoing compensatory changes in reduced electron carrier levels. This emergent behavior, which we named cosubstrate compensation (CSC), enables the ETC to maintain homeostasis over a wide of oxygen levels. When performing CSC, our ETC models recapitulated a classic scaling relationship discovered by Chance [Chance B (1965) J. Gen. Physiol. 49:163-165] relating the extent of oxygen homeostasis to the kinetics of mitochondrial electron transport. Analysis of an in silico mitochondrial respiratory system further showed evidence that CSC constitutes the dominant control strategy for mitochondrial oxygen homeostasis during active respiration. Our findings indicate that CSC constitutes a robust control strategy for homeostasis and adaptation in cellular biochemical networks.

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Additional Information:© 2013 by the Biophysical Society. Submitted July 8, 2012, and accepted for publication January 17, 2013. We thank the Mitchison lab and the Department of Systems Biology at Harvard for providing a stimulating environment for this work, and are grateful to Lea Goentoro, Joe Levine, Mike Springer, Chao Tang, Uri Alon, Tom Rapoport, and Jeremy Gunawardena for discussions and comments. Finally, we thank Daniel Beard for sharing MATLAB code for his mitochondrial ETC model, and for insightful suggestions. P.N. and H.Y.K. conceived and formulated the concept of co-substrate compensation. H.Y.K. developed the mathematical models, performed the simulations, and wrote the paper. T.J.M. provided intellectual guidance. This work was supported by National Institutes of Health grant No. GM023928.
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Official Citation:Hao Yuan Kueh, Philipp Niethammer, Timothy J. Mitchison, Maintenance of Mitochondrial Oxygen Homeostasis by Cosubstrate Compensation, Biophysical Journal, Volume 104, Issue 6, 19 March 2013, Pages 1338-1348, ISSN 0006-3495, 10.1016/j.bpj.2013.01.030.
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:38273
Deposited By: John Wade
Deposited On:03 May 2013 22:58
Last Modified:03 May 2013 22:58

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