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Lethal Mitochondrial Cardiomyopathy in a Hypomorphic Med30 Mouse Mutant Is Ameliorated by Ketogenic Diet

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Lethal Mitochondrial Cardiomyopathy in a Hypomorphic Med30 Mouse Mutant Is Ameliorated by Ketogenic Diet Lethal mitochondrial cardiomyopathy in a hypomorphic Med30 mouse mutant is ameliorated by ketogenic diet Philippe Krebsa,1, Weiwei Fanb, Yen-Hui Chenc, Kimimasa Tobitad, Michael R. Downesb, Malcolm R. Woode, Lei Suna, Xiaohong Lia, Yu Xiaa, Ning Dingb, Jason M. Spaethf, Eva Marie Y. Morescoa, Thomas G. Boyerf, Cecilia Wen Ya Lod, Jeffrey Yenc, Ronald M. Evansb, and Bruce Beutlera,2,3 aDepartment of Genetics and eCore Microscopy Facility, The Scripps Research Institute, La Jolla, CA 92037; bThe Salk Institute, Howard Hughes Medical Institute, La Jolla, CA 92037; cInstitute of Biomedical Sciences, Academia Sinica, 11529 Taipei, Taiwan; dDepartment of Developmental Biology, Rangos Research Center, Pittsburgh, PA 15201; and fDepartment of Molecular Medicine, University of Texas Health Science Center, San Antonio, TX 78245 Contributed by Bruce Beutler, October 31, 2011 (sent for review September 24, 2011) Deficiencies of subunits of the transcriptional regulatory complex sociated with any phenotype in living organisms. In contrast to Mediator generally result in embryonic lethality, precluding study of other models with Mediator deficiencies, homozygous zeitgeist its physiological function. Here we describe a missense mutation in mice are physically indistinguishable from littermates at the time Med30 causing progressive cardiomyopathy in homozygous mice of weaning, but develop progressive cardiomyopathy that is in- that, although viable during lactation, show precipitous lethality 2– variably fatal by 7 wk of age. Mechanistically, the Med30zg mutation 3 wk after weaning. Expression profiling reveals pleiotropic changes causes a progressive and selective decline in the transcription of in transcription of cardiac genes required for oxidative phosphoryla- genes necessary for oxidative phosphorylation (OXPHOS) and tion and mitochondrial integrity. Weaning mice to a ketogenic diet mitochondrial integrity, eventually leading to cardiac failure. Re- extends viability to 8.5 wk. Thus, we establish a mechanistic connec- markably, a ketogenic diet (KD) significantly extends the lifespan tion between Mediator and induction of a metabolic program for of homozygotes. oxidative phosphorylation and fatty acid oxidation, in which lethal cardiomyopathy is mitigated by dietary intervention. Results and Discussion We serendipitously observed conspicuous and frequent pre- heart | metabolism | peroxisome proliferator-activated receptor-γ mature death in a pedigree of C57BL/6J G3 mice homozygous for coactivator-1α ENU-induced mutations. This phenotype was mapped to a 14.4- Mbp critical region on Chromosome 15 (Fig. 1A and Fig. S1)and he Mediator complex encompasses ∼30 proteins necessary ascribed to a single nonsynonymous A-to-T transversion in the Tfor expression of RNA polymerase II-transcribed genes (1), first of the four exons of Med30 (Fig. 1B). The mutation resulted binding simultaneously to Pol II and to gene-specifictranscrip- in an isoleucine to phenylalanine substitution at amino acid 44 of tional activators and promoting preinitiation complex assem- the 178-residue protein. An isoleucine at the corresponding po- bly (2, 3). sition is conserved in MED30 of all vertebrate and invertebrate The fundamental requirement for Mediator in eukaryotic gene species examined (Fig. 1C). Complementation studies between expression is demonstrated by the fact that all mutant alleles of a gene-trap allele of Med30, in which the last exon was deleted murine Mediator subunits generated to date are homozygous le- and the Med30zg allele, did not produce any compound hetero- −/− thal during embryonic development. Med1 mice do not develop zygotes, suggesting the zeitgeist mutation is hypomorphic and further than embryonic day 11.5, and a Med1 hypomorphic mu- embryonic lethal when placed in trans with a null allele of the tant dies before embryonic day 13.5, displaying a plethora of de- same gene (Table S1). velopmental defects (4, 5). Mice deficient in Med24 die before Other components of Mediator are critical for heart develop- embryonic day 9.5 with severe developmental abnormalities (6). ment and anatomy in mice (4–6). In humans, truncation or mis- Med21 is essential for survival past the blastocyst stage of mouse sense mutations in MED13L, a MED13 homolog, have been embryonic development (7). Other lethal effects have been re- observed in some patients with transposition of the great arteries ported during embryogenesis in mice and zebrafish, with trunca- (12). In contrast, Med30zg/zg mice showed no developmental tions of Cdk8 and Med12, respectively (8, 9). So far, only Med1 anomaly per se, only progressive heart failure postweaning. How- fi fi zg/zg and Med24 de ciencies permit survival to a suf ciently differen- ever, Med30 mice were born to heterozygous parents at a fre- tiated stage of development in which analysis of distinct tissues quency beneath expectation, indicating that attrition of homo- is possible. In humans, missense mutations of MED12 lead to zygotes occurs prenatally (Table S2). Genotyping of embryos at neurological abnormalities observed in Opitz-Kaveggia syndrome gestational day 15.5 suggested that death may occur after this (10) or Lujan-Fryns syndrome (11). Understanding the mecha- time point (Table S2). nisms and consequences of Mediator binding to various tran- scription factors in the context of cell or tissue type, developmen- tal stage, and biological process has thus been hampered by the Author contributions: P.K., M.R.D., C.W.Y.L., J.Y., R.M.E., and B.B. designed research; P.K., embryonic lethality of Mediator mutants. W.F., Y.-H.C., K.T., M.R.W., L.S., and X.L. performed research; W.F., M.R.D., X.L., N.D., In mammals, Mediator was first isolated by virtue of its direct J.M.S., T.G.B., C.W.Y.L., J.Y., R.M.E., and B.B. contributed new reagents/analytic tools; association with nuclear hormone receptors in complexes, in- P.K., W.F., Y.-H.C., K.T., M.R.W., Y.X., C.W.Y.L., J.Y., R.M.E., and B.B. analyzed data; and P.K., E.M.Y.M., R.M.E., and B.B. wrote the paper. cluding TRAP (thyroid hormone receptor-associated proteins) fl and DRIP (vitamin D receptor-interacting proteins), and was The authors declare no con ict of interest. 1 shown to play a key role in hormone-dependent signaling (2, 3). Present address: Division of Experimental Pathology, Institute of Pathology, University of Bern, Bern, Switzerland. However, the physiological relevance of individual complex com- 2Present address: Center for Genetics of Host Defense, University of Texas Southwestern ponents to metabolism or disease has only recently begun to Medical Center, Dallas, TX 75390. emerge. Here we describe zeitgeist (zg), a recessive N-ethyl-N- 3To whom correspondence should be addressed. E-mail: Bruce.Beutler@UTSouthwestern. nitrosurea (ENU)-induced phenotype attributed to a missense edu. mutation in Med30. Initially isolated from the TRAP complex (1), This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. MED30 is a component of the Mediator core thus far not as- 1073/pnas.1117835108/-/DCSupplemental. 19678–19682 | PNAS | December 6, 2011 | vol. 108 | no. 49 www.pnas.org/cgi/doi/10.1073/pnas.1117835108 Downloaded by guest on September 27, 2021 100 Med30+/+ Med30zg/zg 0.6 A Littermates B +/+ A D 80 0.5 60 Med30 40 C57BL/6J x 0.4 % survival C3H/HeN F1 20 zg/zg B LVIDd (mm) 0.3 0 0 2530354045 * days Med30 0.2 C 20 30 40 50 60 Mouse 39 E T V Q D I V Y R T M E E Med30+/+ Med30zg/zg 100 Rat 39 E T V Q D I V Y R T M E Ao Ao Chimpanzee 39 E T V Q D I V Y R T M E C 80 E T V Q D I V Y R T M E LV Human 39 d8 LV X. tropicalis 43 E T V Q D I V F R T M E RV RV 60 Danio rerio 55 E T V Q D I V T R T M E 40 Fruit fly 128 E T V Q D I A S R F Q E EF (%) Ao Ao 20 LV D Med30+/+ Med30zg/zg d21 LV RV 0 RV 20 30 40 50 60 +/+ Age (d) Med30 zg/zg Ao Ao Med30 LV LV d32 RV RV Fig. 2. Zeitgeist homozygotes develop myocardial fibrosis and heart failure. Histological and functional analysis of mutant hearts shortly before death. (A) H&E staining of myocardium. (Scale bars, 100 μm.) (B) Masson’s trichrome Fig. 1. Zeitgeist phenotype; identification of the mutation and anatomical staining of the ventricular wall. Arrows show regions with cardiomyocyte fi μ analysis of the heart. (A) Kaplan–Meier survival curve of C57BL/6J × C3H/HeN necrosis and asterisks areas of prominent brosis. (Scale bars, 100 m.) (C) F1 hybrid zeitgeist mutants (n = 41; **P = 0.058). (B) Chromatogram showing Echocardiography of mutant and control hearts. (Scale bars, 0.5 cm.) (D)LV an A195T transversion in exon 1 of Med30 (NM_027212). (C) The zeitgeist internal dimension in diastole (LVIDd) and ejection fraction (EF) as a function mutation causes an isoleucine to phenylalanine substitution at amino acid of age. n = 3 for wild-type; n = 5 for mutant mice. 44, a residue conserved in all species known to possess a Med30 gene. (D) The zeitgeist mutants displayed dilated and flaccid ventricles compared with control littermates (H&E staining). (Scale bars, 2 mm.) (F) MRI analysis of features that became apparent after 4 wk of age (Fig. 3 C and D). mutant and control hearts at the indicated ages shown in a coronal plane. The degree and extent of mitochondrial alterations were irreg- Ao, aorta; LV, left ventricle, RV, right ventricle. (Scale bar, 5 mm.) ular, both among neighboring cells and within single cardio- myocytes (Fig. 3 B and E). In the most severe cases, such changes fi zg/zg were associated with disappearance of myo brillar structure Dissection of moribund Med30 mice revealed a dilated (Fig.
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