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Dysfunctional bioenergetics has emerged as a key feature in many chronic pathologies such as diabetes and cardiovascular disease. This has led to the mitochondrial paradigm in which it has been proposed that mtDNA sequence variation contributes to disease susceptibility. In the present study we show a novel animal model of mtDNA polymorphisms, the MNX (mitochondrial–nuclear exchange) mouse, in which the mtDNA from the C3H/HeN mouse has been inserted on to the C57/BL6 nuclear background and vice versa to test this concept. Our data show a major contribution of the C57/BL6 mtDNA to the susceptibility to the pathological stress of cardiac volume overload which is independent of the nuclear background. Mitochondria harbouring the C57/BL6J mtDNA generate more ROS (reactive oxygen species) and have a higher mitochondrial membrane potential relative to those with C3H/HeN mtDNA, independent of nuclear background. We propose this is the primary mechanism associated with increased bioenergetic dysfunction in response to volume overload. In summary, these studies support the ‘mitochondrial paradigm’ for the development of disease susceptibility, and show that the mtDNA modulates cellular bioenergetics, mitochondrial ROS generation and susceptibility to cardiac stress.
This research was originally published in Biochemical Journal. Fetterman JL, Zelickson BR, Johnson LW, Moellering DR, Westbrook DG, Pompilius M, Sammy MJ, Salman ED, Johnson M, Dunham-Snary KJ, Cao X, Bradley WE, Zhang J, Wei CC, Chacko B, Schurr TG, Kesterson RA, Dell’Italia LJ, Darley-Usmar VM, Welch DR, Ballinger SW. Mitochondrial genetic background modulates bioenergetics and susceptibility to acute cardiac volume overload. Biochemical Journal 455: 157–167. © the Biochemical Society
bioenergetics, disease susceptibility, mitochondria, mtDNA, oxidative stress
Fetterman, J. L., Zelickson, B. R., Johnson, L. W., Moellering, D. R., Westbrook, D. G., Pompilius, M., Sammy, M. J., Johnson, M., Dunham‑Snary, K. J., Cao∥, X., Bradley, W. E., Zhang, J., Wei, C., Chacko, B., Schurr, T. G., Kesterson, R. A., Dell’italia, L. J., Darley‑Usmar, V. M., Welch, D. R., & Ballinger, S. W. (2013). Mitochondrial Genetic Background Modulates Bioenergetics and Susceptibility to Acute Cardiac Volume Overload. Biochemical Journal, 455 (2), 157-167. https://doi.org/10.1042/BJ20130029
Date Posted: 18 December 2014
This document has been peer reviewed.