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Heart Mitochondrial Proteome - The Failing Heart Relies on Ketone Bodies as a Fuel

ABSTRACT: Isolation of Heart Mitochondria of defined stages of pressure overload-induced heart failure in mice

INSTRUMENT(S): LTQ Orbitrap Velos

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Heart

DISEASE(S): Cardiovascular System Disease

SUBMITTER: Marcus Krueger

LAB HEAD: Krueger

PROVIDER: PXD001820 | Pride | 2016-05-09

REPOSITORIES: Pride

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			Action	DRS
	20110121MK_Aubert_Mito_crude_TAC_13_01.raw	Raw
	20110121MK_Aubert_Mito_crude_TAC_13_02.raw	Raw
	20110121MK_Aubert_Mito_crude_TAC_13_03.raw	Raw
	20110121MK_Aubert_Mito_crude_TAC_13_04.raw	Raw
	20110121MK_Aubert_Mito_crude_TAC_13_05.raw	Raw

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The Failing Heart Relies on Ketone Bodies as a Fuel.

Aubert Gregory G Martin Ola J OJ Horton Julie L JL Lai Ling L Vega Rick B RB Leone Teresa C TC Koves Timothy T Gardell Stephen J SJ Krüger Marcus M Hoppel Charles L CL Lewandowski E Douglas ED Crawford Peter A PA Muoio Deborah M DM Kelly Daniel P DP

Circulation 20160127 8

<h4>Background</h4>Significant evidence indicates that the failing heart is energy starved. During the development of heart failure, the capacity of the heart to utilize fatty acids, the chief fuel, is diminished. Identification of alternate pathways for myocardial fuel oxidation could unveil novel strategies to treat heart failure.<h4>Methods and results</h4>Quantitative mitochondrial proteomics was used to identify energy metabolic derangements that occur during the development of cardiac hype ...[more]

PMID: 26819376

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The Failing Heart Relies on Ketone Bodies as a Fuel.

Project description:BackgroundSignificant evidence indicates that the failing heart is energy starved. During the development of heart failure, the capacity of the heart to utilize fatty acids, the chief fuel, is diminished. Identification of alternate pathways for myocardial fuel oxidation could unveil novel strategies to treat heart failure.Methods and resultsQuantitative mitochondrial proteomics was used to identify energy metabolic derangements that occur during the development of cardiac hypertrophy and heart failure in well-defined mouse models. As expected, the amounts of proteins involved in fatty acid utilization were downregulated in myocardial samples from the failing heart. Conversely, expression of β-hydroxybutyrate dehydrogenase 1, a key enzyme in the ketone oxidation pathway, was increased in the heart failure samples. Studies of relative oxidation in an isolated heart preparation using ex vivo nuclear magnetic resonance combined with targeted quantitative myocardial metabolomic profiling using mass spectrometry revealed that the hypertrophied and failing heart shifts to oxidizing ketone bodies as a fuel source in the context of reduced capacity to oxidize fatty acids. Distinct myocardial metabolomic signatures of ketone oxidation were identified.ConclusionsThese results indicate that the hypertrophied and failing heart shifts to ketone bodies as a significant fuel source for oxidative ATP production. Specific metabolite biosignatures of in vivo cardiac ketone utilization were identified. Future studies aimed at determining whether this fuel shift is adaptive or maladaptive could unveil new therapeutic strategies for heart failure.

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Proteomics on sera of mice following local high-dose heart irradiation

Project description:Background and Purpose: Cardiotoxicity is a well-known adverse effect of radiation therapy. Measurable abnormalities in the heart function indicate advanced and often irreversible heart damage. Therefore, early detection of cardiac toxicity is necessary to delay and alleviate the development of the disease. The present study investigated long-term serum proteome alterations following local heart irradiation using a mouse model with the aim to detect biomarkers of radiation-induced cardiac toxicity. Materials and Methods: Serum samples from C57BL/6J mice were collected 20 weeks after local heart irradiation with 8 Gy or 16 Gy X-ray; the controls were sham-irradiated. The samples were analyzed by quantitative proteomics based on data-independent acquisition mass spectrometry. The proteomics data were further investigated using bioinformatics and ELISA. Results: The analysis showed radiation-induced changes in the level of several serum proteins involved in the acute phase response, inflammation and cholesterol metabolism. We found significantly enhanced expression of pro-inflammatory cytokines (TNF-, TGF-, IL-1 and IL-6) in the serum of the irradiated mice. The level of free fatty acids, total cholesterol, low density lipoprotein (LDL) and oxidized LDL was increased whereas that of high density lipoprotein was decreased by irradiation. Conclusions: This study provides information on systemic effects of heart irradiation. It elucidates a radiation fingerprint in the serum that may be used to elucidate adverse cardiac effects after radiation therapy.

2021-09-10 | PXD024446 | Pride

Mitochondrial interactome quantitation reveals structural changes in metabolic machinery in failing murine heart

Project description:Advancements of cross-linking mass spectrometry (XL-MS) for structural analysis of proteins bridges the gap between purified systems and native tissue environments. Here, we utilize isobaric quantitative protein interaction reporter technology (iqPIR) to further extend XL-MS to the first system-wide comparative study of mitochondrial proteins from healthy and diseased murine hearts. The failing heart interactome includes 544 statistically significant cross-linked peptide pairs altered in disease condition. Structural insight into ketone oxidation metabolons, OXPHOS machinery, and nucleotide transporter hybrid-conformations, support mitochondrial remodeling in failing heart while bringing forth new hypotheses for pathological mechanisms. Application of quantitative cross-linking technology in live tissue provides molecular-level insight to complex biological systems difficult to model in cell culture, thus providing a valuable resource for study of human diseases.

2022-08-02 | PXD027757 | Pride

Mitochondrial Protein Hyperacetylation in the Failing Heart

Project description:Mitochondrial proteomics was used to identify energy metabolic derangements that occur during the early stages of heart failure in well-defined mouse models. Levels of β-hydroxybutyrate dehydrogenase 1 (BDH1), a key enzyme in ketone oxidation, was upregulated. 13C-substrate flux studies and metabolomic profiling confirmed that the hypertrophied and early stage failing heart shifts to ketone bodies as a fuel source in the context of reduced oxidation of fatty acids, the chief substrate for the normal heart. This fuel shift is associated with an expansion of the acetyl pool and reduced levels of NAD+ levels resulting in increased mitochondrial protein acetylation. Myocardium of humans with heart failure also exhibited mitochondrial protein hyperacetylation. We propose that a shift to ketones as a fuel source leads to maladaptive bioenergetic consequences during the development of heart failure.

2016-02-26 | PXD001652 | Pride

Gene expression data from murine heart ventricles E12.5 with and without cardiomyocyte-specific expression of constitutively active IKK2

Project description:The transcription factor NF-κB has been associated with a range of pathological conditions of the heart, mainly based on its function as a master regulator of inflammation and pro-survival factor. Here, we addressed the question what effects activation of NF-κB can have during murine heart development. We expressed a constitutively active (CA) mutant of IKK2, the kinase activating canonical NF-κB signaling, specifically in cardiomyocytes under the control of the α-myosin heavy chain promoter. Expression of IKK2-CA resulted in embryonic lethality around E13. Embryos showed defects in compact zone formation and the contractile apparatus, and overall were characterized by widespread inflammation with infiltration of myeloid cells. Gene expression analysis at E12.5 suggested an interferon type I signature, with increased expression of interferon regulatory factors.

2015-10-14 | E-MTAB-3971 | biostudies-arrayexpress

Comprehensive quantification of fuel use by the failing and nonfailing human heart.

Project description:The heart consumes circulating nutrients to fuel lifelong contraction, but a comprehensive mapping of human cardiac fuel use is lacking. We used metabolomics on blood from artery, coronary sinus, and femoral vein in 110 patients with or without heart failure to quantify the uptake and release of 277 metabolites, including all major nutrients, by the human heart and leg. The heart primarily consumed fatty acids and, unexpectedly, little glucose; secreted glutamine and other nitrogen-rich amino acids, indicating active protein breakdown, at a rate ~10 times that of the leg; and released intermediates of the tricarboxylic acid cycle, balancing anaplerosis from amino acid breakdown. Both heart and leg consumed ketones, glutamate, and acetate in direct proportionality to circulating levels, indicating that availability is a key driver for consumption of these substrates. The failing heart consumed more ketones and lactate and had higher rates of proteolysis. These data provide a comprehensive and quantitative picture of human cardiac fuel use.

| S-EPMC7871704 | biostudies-literature

Gene expression in ischemic, end-stage failing and non-failing human hearts

Project description:A goal of this study was to identify and investigate previously unrecognized components of the remodeling process in the progression to heart failure by comparing gene expression in ischemic, failing (F) to non-failing (NF) hearts. These results also were compared to the changes observed in a proteomic analysis of F and NF hearts. RNA extracted from the left ventricle was hybridized to Affymetrix arrays to identify gene expression differences in ischemic, end-stage failing versus non-failing hearts. biological replicate: LV_NF_001, LV_NF002, LV_NF004, LV_NF005 biological replicate: LV_F_003, LV_F005, LV_F009, LV_F006

2016-02-08 | E-GEOD-76701 | biostudies-arrayexpress

Gene expression profiles in the heart tissues of heart-specific Bmal1 knockout mice

Project description:Mice without cardiac Bmal1 function develop severe progressive heart failure with age. To examine the mechanism underlying the failing heart phenotype observed in heart-specific Bmal1 knockout mice, microarray analyses were performed. The analyses revealed that broad classes of genes regulating cellular energy metabolism were upregulated or downregulated in the heart tissues of heart-specific Bmal1 knockout mice compared with those of control animals. Heart total RNA extracted from six animals per genotype (control and heart-specific Bmal1 knockout) was pooled and then used for a microarray analysis.

2014-09-27 | E-GEOD-61787 | biostudies-arrayexpress

RNA-Sequencing shows novel transcriptomic signatures in failing and non-failing human heart

Project description:The knowledge of an expression network signature in end-stage heart failure (HF) diseased hearts may offer important insights into the complex pathogenesis of advanced cardiac failure, as well as it may provide potential targets for therapeutic intervention. In this study, the NGS sequencing of RNA (RNA-Seq) method was employed to obtain the whole transcriptome of cardiac tissues from transplant recipients with advanced stage of HF. The analysis of RNA-Seq data presents novel challenges and many methods have been developed for the purpose of mapping reads to genomic features and quantifying gene expression. The main goal of this work was to identify, characterize and catalogue all the transcripts expressed within cardiac tissue and to quantify the differential expression of transcripts in both physio- and pathological conditions through whole transcriptome analyses. Expression levels, differential splicing, allele-specific expression, RNA editing and fusion transcripts constitute important information when comparing samples for disease related studies. Analysis methods for RNA-Seq data are continuing to evolve. Thus, in order to find the best solution for filter generated list of differentially expressed genes, an informatic approach of NOISeq BIO method has been applied in this RNA-Seq analysis. Most of the genes obtained by filtering differentially expressed gene list, have been experimentally validated by Real time RT-PCR. Noteworthy, these findings provide valuable resources for further studies of the molecular mechanisms involved in heart ischemic response thus leading to potential novel biomarkers and targets for therapeutic intervention in the onset and progression of cardiomyopathies. Heart biopsies from candidates for solid organ transplantation were collected and their RNA samples were used for high-throughput sequencing purposes. Libraries were sequenced on the Illumina HiSeq2000 NGS platform.

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Mitochondrial interactome quantitation with dead-end peptides in failing murine heart

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