Lethal mitochondrial cardiomyopathy in a hypomorphic Med30 mouse mutant is ameliorated by ketogenic diet

Philippe Krebs; Weiwei Fan; Yen Hui Chen; Kimimasa Tobita; Michael R. Downes; Malcolm R. Wood; Lei Sun; Xiaohong Li; Yu Xia; Ning Ding; Jason M. Spaeth; Eva Marie Y Moresco; Thomas G. Boyer; Cecilia Wen Ya Lo; Jeffrey Yen; Ronald M. Evans; Bruce Beutler

doi:10.1073/pnas.1117835108

Lethal mitochondrial cardiomyopathy in a hypomorphic Med30 mouse mutant is ameliorated by ketogenic diet

Philippe Krebs, Weiwei Fan, Yen Hui Chen, Kimimasa Tobita, Michael R. Downes, Malcolm R. Wood, Lei Sun, Xiaohong Li, Yu Xia, Ning Ding, Jason M. Spaeth, Eva Marie Y Moresco, Thomas G. Boyer, Cecilia Wen Ya Lo, Jeffrey Yen, Ronald M. Evans, Bruce Beutler

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52 Scopus citations

Abstract

Deficiencies of subunits of the transcriptional regulatory complex Mediator generally result in embryonic lethality, precluding study of its physiological function. Here we describe a missense mutation in Med30 causing progressive cardiomyopathy in homozygous mice that, although viable during lactation, show precipitous lethality 2-3 wk afterweaning. Expression profiling reveals pleiotropic changes in transcription of cardiac genes required for oxidative phosphorylation and mitochondrial integrity. Weaning mice to a ketogenic diet extends viability to 8.5 wk. Thus, we establish a mechanistic connection between Mediator and induction of a metabolic program for oxidative phosphorylation and fatty acid oxidation, in which lethal cardiomyopathy is mitigated by dietary intervention.

Original language	English (US)
Pages (from-to)	19678-19682
Number of pages	5
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	108
Issue number	49
DOIs	https://doi.org/10.1073/pnas.1117835108
State	Published - Dec 6 2011

Keywords

Heart
Metabolism
Peroxisome proliferator-activated receptor-γ coactivator-1α

ASJC Scopus subject areas

General

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10.1073/pnas.1117835108

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Krebs, P., Fan, W., Chen, Y. H., Tobita, K., Downes, M. R., Wood, M. R., Sun, L., Li, X., Xia, Y., Ding, N., Spaeth, J. M., Moresco, E. M. Y., Boyer, T. G., Lo, C. W. Y., Yen, J., Evans, R. M., & Beutler, B. (2011). Lethal mitochondrial cardiomyopathy in a hypomorphic Med30 mouse mutant is ameliorated by ketogenic diet. Proceedings of the National Academy of Sciences of the United States of America, 108(49), 19678-19682. https://doi.org/10.1073/pnas.1117835108

Krebs, P, Fan, W, Chen, YH, Tobita, K, Downes, MR, Wood, MR, Sun, L, Li, X, Xia, Y, Ding, N, Spaeth, JM, Moresco, EMY, Boyer, TG, Lo, CWY, Yen, J, Evans, RM & Beutler, B 2011, 'Lethal mitochondrial cardiomyopathy in a hypomorphic Med30 mouse mutant is ameliorated by ketogenic diet', Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 49, pp. 19678-19682. https://doi.org/10.1073/pnas.1117835108

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abstract = "Deficiencies of subunits of the transcriptional regulatory complex Mediator generally result in embryonic lethality, precluding study of its physiological function. Here we describe a missense mutation in Med30 causing progressive cardiomyopathy in homozygous mice that, although viable during lactation, show precipitous lethality 2-3 wk afterweaning. Expression profiling reveals pleiotropic changes in transcription of cardiac genes required for oxidative phosphorylation and mitochondrial integrity. Weaning mice to a ketogenic diet extends viability to 8.5 wk. Thus, we establish a mechanistic connection between Mediator and induction of a metabolic program for oxidative phosphorylation and fatty acid oxidation, in which lethal cardiomyopathy is mitigated by dietary intervention.",

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AU - Downes, Michael R.

AU - Wood, Malcolm R.

AU - Sun, Lei

AU - Li, Xiaohong

AU - Xia, Yu

AU - Ding, Ning

AU - Spaeth, Jason M.

AU - Moresco, Eva Marie Y

AU - Boyer, Thomas G.

AU - Lo, Cecilia Wen Ya

AU - Yen, Jeffrey

AU - Evans, Ronald M.

AU - Beutler, Bruce

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AB - Deficiencies of subunits of the transcriptional regulatory complex Mediator generally result in embryonic lethality, precluding study of its physiological function. Here we describe a missense mutation in Med30 causing progressive cardiomyopathy in homozygous mice that, although viable during lactation, show precipitous lethality 2-3 wk afterweaning. Expression profiling reveals pleiotropic changes in transcription of cardiac genes required for oxidative phosphorylation and mitochondrial integrity. Weaning mice to a ketogenic diet extends viability to 8.5 wk. Thus, we establish a mechanistic connection between Mediator and induction of a metabolic program for oxidative phosphorylation and fatty acid oxidation, in which lethal cardiomyopathy is mitigated by dietary intervention.

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KW - Metabolism

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Lethal mitochondrial cardiomyopathy in a hypomorphic Med30 mouse mutant is ameliorated by ketogenic diet

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