Dataset Information

Age-Related Disruption of the Proteome and Acetylome in Mouse Hearts Correlates with Differential Loss of Function that is Attenuated by SS-31 and NMN

ABSTRACT: We analyzed the effects of aging on protein abundance and acetylation, as well as the ability of the mitochondrial-targeted drugs SS-31 and NMN to reverse age-related changes, in mouse hearts. Both drugs had a modest effect on restoring the abundance and acetylation of proteins that are lost with age but only NMN reduced acetylation in a subset of proteins which increased acetylation with age. Primarily, these age-related increases in protein acetylation were in mitochondrial pathways such as mitochondrial dysfunction, oxidative phosphorylation, and TCA cycle signaling. We further assessed how these age-related changes correlated with diastolic function (Ea/Aa) and systolic function (fractional shortening under higher workload) measurements from echocardiography. These results show that diastolic and systolic function in old age correlate inversely with the abundance of a specific subset of proteins. This could indicate that the heart proteome may adapt to preserve diastolic or systolic function with age but cannot preserve both. This adds further evidence to our previous report that SS-31 provides benefit to diastolic function and NMN to systolic function and that the greatest benefit may be when both are administered together, as the combination provides a mechanism to improve both aspects of heart function simultaneously.

ORGANISM(S): Mus Musculus

SUBMITTER: Richard Johnson

PROVIDER: PXD027458 | panorama | Tue Aug 02 00:00:00 BST 2022

REPOSITORIES: PanoramaPublic

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Publications

Age-related disruption of the proteome and acetylome in mouse hearts is associated with loss of function and attenuated by elamipretide (SS-31) and nicotinamide mononucleotide (NMN) treatment.

Whitson Jeremy A JA Johnson Richard R Wang Lu L Bammler Theo K TK Imai Shin-Ichiro SI Zhang Huiliang H Fredrickson Jeanne J Latorre-Esteves Elena E Bitto Alessandro A MacCoss Michael J MJ Rabinovitch Peter S PS

GeroScience 20220413 3

We analyzed the effects of aging on protein abundance and acetylation, as well as the ability of the mitochondrial-targeted drugs elamipretide (SS-31) and nicotinamide mononucleotide (NMN) to reverse aging-associated changes in mouse hearts. Both drugs had a modest effect on restoring the abundance and acetylation of proteins that are altered with age, while also inducing additional changes. Age-related increases in protein acetylation were predominantly in mitochondrial pathways such as mitocho ...[more]

PMID: 35416576

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Project description:This model is from the article: A metabolic model of the mitochondrion and its use in modelling diseases of the tricarboxylic acid cycle. Smith AC, Robinson AJ. BMC Syst Biol. 2011 Jun 29;5(1):102. 21714867 , Abstract: BACKGROUND:Mitochondria are a vital component of eukaryotic cells and their dysfunction is implicated in a large number of metabolic, degenerative and age-related human diseases. The mechanism or these disorders can be difficult to elucidate due to the inherent complexity of mitochondrial metabolism. To understand how mitochondrial metabolic dysfunction contributes to these diseases, a metabolic model of a human heart mitochondrion was created. RESULTS: A new model of mitochondrial metabolism was built on the principle of metabolite availability using MitoMiner, a mitochondrial proteomics database, to evaluate the subcellular localisation of reactions that have evidence for mitochondrial localisation. Extensive curation and manual refinement was used to create a model called iAS253, containing 253 reactions, 245 metabolites and 89 transport steps across the inner mitochondrial membrane. To demonstrate the predictive abilities of the model, flux balance analysis was used to calculate metabolite fluxes under normal conditions and to simulate three metabolic disorders that affect the TCA cycle: fumarase deficiency, succinate dehydrogenase deficiency and alpha-ketoglutarate dehydrogenase deficiency. CONCLUSION: The results of simulations using the new model corresponded closely with phenotypic data under normal conditions and provided insight into the complicated and unintuitive phenotypes of the three disorders, including the effect of interventions that may be of therapeutic benefit, such as low glucose diets or amino acid supplements. The model offers the ability to investigate other mitochondrial disorders and can provide the framework for the integration of experimental data in future studies. Created by Anthony C. Smith (Mon Mar 14 11:03:11 2011) MRC - Mitochondrial Biology Unit, Cambridge, UK. acs@mrc-mbu.cam.ac.uk This metabolic network is a stocihiometric model of a human heart mitochondrion. Identifiers are KEGG Ids. This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2011 The BioModels.net Team. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information. In summary, you are entitled to use this encoded model in absolutely any manner you deem suitable, verbatim, or with modification, alone or embedded it in a larger context, redistribute it, commercially or not, in a restricted way or not.. To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.

Dataset Information

Age-Related Disruption of the Proteome and Acetylome in Mouse Hearts Correlates with Differential Loss of Function that is Attenuated by SS-31 and NMN

Publications

Age-related disruption of the proteome and acetylome in mouse hearts is associated with loss of function and attenuated by elamipretide (SS-31) and nicotinamide mononucleotide (NMN) treatment.

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