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Respiratory Phenomics across Multiple Models of Protein Hyperacylation in Cardiac Mitochondria Reveals a Marginal Impact on Bioenergetics

Acyl CoA metabolites derived from the catabolism of carbon fuels can react with lysine residues of mitochondrial proteins, giving rise to a large family of post-translational modifications (PTMs). Mass spectrometry-based detection of thousands of acyl-PTMs scattered throughout the proteome has estab...

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Autores principales: Fisher-Wellman, Kelsey H., Draper, James A., Davidson, Michael T., Williams, Ashley S., Narowski, Tara M., Slentz, Dorothy H., Ilkayeva, Olga R., Stevens, Robert D., Wagner, Gregory R., Najjar, Rami, Hirschey, Mathew D., Thompson, J. Will, Olson, David P., Kelly, Daniel P., Koves, Timothy R., Grimsrud, Paul A., Muoio, Deborah M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6478502/
https://www.ncbi.nlm.nih.gov/pubmed/30726738
http://dx.doi.org/10.1016/j.celrep.2019.01.057
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author Fisher-Wellman, Kelsey H.
Draper, James A.
Davidson, Michael T.
Williams, Ashley S.
Narowski, Tara M.
Slentz, Dorothy H.
Ilkayeva, Olga R.
Stevens, Robert D.
Wagner, Gregory R.
Najjar, Rami
Hirschey, Mathew D.
Thompson, J. Will
Olson, David P.
Kelly, Daniel P.
Koves, Timothy R.
Grimsrud, Paul A.
Muoio, Deborah M.
author_facet Fisher-Wellman, Kelsey H.
Draper, James A.
Davidson, Michael T.
Williams, Ashley S.
Narowski, Tara M.
Slentz, Dorothy H.
Ilkayeva, Olga R.
Stevens, Robert D.
Wagner, Gregory R.
Najjar, Rami
Hirschey, Mathew D.
Thompson, J. Will
Olson, David P.
Kelly, Daniel P.
Koves, Timothy R.
Grimsrud, Paul A.
Muoio, Deborah M.
author_sort Fisher-Wellman, Kelsey H.
collection PubMed
description Acyl CoA metabolites derived from the catabolism of carbon fuels can react with lysine residues of mitochondrial proteins, giving rise to a large family of post-translational modifications (PTMs). Mass spectrometry-based detection of thousands of acyl-PTMs scattered throughout the proteome has established a strong link between mitochondrial hyperacylation and cardiometabolic diseases; however, the functional consequences of these modifications remain uncertain. Here, we use a comprehensive respiratory diagnostics platform to evaluate three disparate models of mitochondrial hyperacylation in the mouse heart caused by genetic deletion of malonyl CoA decarboxylase (MCD), SIRT5 demalonylase and desuccinylase, or SIRT3 deacetylase. In each case, elevated acylation is accompanied by marginal respiratory phenotypes. Of the >60 mitochondrial energy fluxes evaluated, the only outcome consistently observed across models is a ~15% decrease in ATP synthase activity. In sum, the findings suggest that the vast majority of mitochondrial acyl PTMs occur as stochastic events that minimally affect mitochondrial bioenergetics.
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spelling pubmed-64785022019-04-23 Respiratory Phenomics across Multiple Models of Protein Hyperacylation in Cardiac Mitochondria Reveals a Marginal Impact on Bioenergetics Fisher-Wellman, Kelsey H. Draper, James A. Davidson, Michael T. Williams, Ashley S. Narowski, Tara M. Slentz, Dorothy H. Ilkayeva, Olga R. Stevens, Robert D. Wagner, Gregory R. Najjar, Rami Hirschey, Mathew D. Thompson, J. Will Olson, David P. Kelly, Daniel P. Koves, Timothy R. Grimsrud, Paul A. Muoio, Deborah M. Cell Rep Article Acyl CoA metabolites derived from the catabolism of carbon fuels can react with lysine residues of mitochondrial proteins, giving rise to a large family of post-translational modifications (PTMs). Mass spectrometry-based detection of thousands of acyl-PTMs scattered throughout the proteome has established a strong link between mitochondrial hyperacylation and cardiometabolic diseases; however, the functional consequences of these modifications remain uncertain. Here, we use a comprehensive respiratory diagnostics platform to evaluate three disparate models of mitochondrial hyperacylation in the mouse heart caused by genetic deletion of malonyl CoA decarboxylase (MCD), SIRT5 demalonylase and desuccinylase, or SIRT3 deacetylase. In each case, elevated acylation is accompanied by marginal respiratory phenotypes. Of the >60 mitochondrial energy fluxes evaluated, the only outcome consistently observed across models is a ~15% decrease in ATP synthase activity. In sum, the findings suggest that the vast majority of mitochondrial acyl PTMs occur as stochastic events that minimally affect mitochondrial bioenergetics. 2019-02-05 /pmc/articles/PMC6478502/ /pubmed/30726738 http://dx.doi.org/10.1016/j.celrep.2019.01.057 Text en This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
Fisher-Wellman, Kelsey H.
Draper, James A.
Davidson, Michael T.
Williams, Ashley S.
Narowski, Tara M.
Slentz, Dorothy H.
Ilkayeva, Olga R.
Stevens, Robert D.
Wagner, Gregory R.
Najjar, Rami
Hirschey, Mathew D.
Thompson, J. Will
Olson, David P.
Kelly, Daniel P.
Koves, Timothy R.
Grimsrud, Paul A.
Muoio, Deborah M.
Respiratory Phenomics across Multiple Models of Protein Hyperacylation in Cardiac Mitochondria Reveals a Marginal Impact on Bioenergetics
title Respiratory Phenomics across Multiple Models of Protein Hyperacylation in Cardiac Mitochondria Reveals a Marginal Impact on Bioenergetics
title_full Respiratory Phenomics across Multiple Models of Protein Hyperacylation in Cardiac Mitochondria Reveals a Marginal Impact on Bioenergetics
title_fullStr Respiratory Phenomics across Multiple Models of Protein Hyperacylation in Cardiac Mitochondria Reveals a Marginal Impact on Bioenergetics
title_full_unstemmed Respiratory Phenomics across Multiple Models of Protein Hyperacylation in Cardiac Mitochondria Reveals a Marginal Impact on Bioenergetics
title_short Respiratory Phenomics across Multiple Models of Protein Hyperacylation in Cardiac Mitochondria Reveals a Marginal Impact on Bioenergetics
title_sort respiratory phenomics across multiple models of protein hyperacylation in cardiac mitochondria reveals a marginal impact on bioenergetics
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6478502/
https://www.ncbi.nlm.nih.gov/pubmed/30726738
http://dx.doi.org/10.1016/j.celrep.2019.01.057
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