Proteomic and biochemical studies of lysine malonylation suggest its malonic aciduria-associated regulatory role in mitochondrial function and fatty acid oxidation

G. Colak, O. Pougovkina, L. Dai, M. Tan, H. te Brinke, H. Huang, R.J. Wanders, J.W. Locasale, D.B. Lombard, V.C.J. de Boer, Y. Zhao

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Abstract

The protein substrates of sirtuin 5-regulated lysine malonylation (Kmal) remain unknown, hindering its functional analysis. In this study, we carried out proteomic screening, which identified 4042 Kmal sites on 1426 proteins in mouse liver and 4943 Kmal sites on 1822 proteins in human fibroblasts. Increased malonyl-CoA levels in malonyl-CoA decarboxylase (MCD)-deficient cells induces Kmal levels in substrate proteins. We identified 461 Kmal sites showing more than a 2-fold increase in response to MCD deficiency as well as 1452 Kmal sites detected only in MCD−/− fibroblast but not MCD+/+ cells, suggesting a pathogenic role of Kmal in MCD deficiency. Cells with increased lysine malonylation displayed impaired mitochondrial function and fatty acid oxidation, suggesting that lysine malonylation plays a role in pathophysiology of malonic aciduria. Our study establishes an association between Kmal and a genetic disease and offers a rich resource for elucidating the contribution of the Kmal pathway and malonyl-CoA to cellular physiology and human diseases.
Original languageEnglish
Pages (from-to)3056-3071
JournalMolecular and Cellular Proteomics
Volume14
Issue number11
DOIs
Publication statusPublished - 2015

Fingerprint

malonyl-CoA decarboxylase
Proteomics
Lysine
Fatty Acids
Malonyl Coenzyme A
Oxidation
Fibroblasts
Proteins
Inborn Genetic Diseases
Functional analysis
Physiology
Substrates
Liver
Screening
Malonic aciduria
Association reactions

Keywords

  • Proteomic
  • lysine malonylation
  • mitochondrial function
  • fatty acid oxydation

Cite this

Colak, G. ; Pougovkina, O. ; Dai, L. ; Tan, M. ; te Brinke, H. ; Huang, H. ; Wanders, R.J. ; Locasale, J.W. ; Lombard, D.B. ; de Boer, V.C.J. ; Zhao, Y. / Proteomic and biochemical studies of lysine malonylation suggest its malonic aciduria-associated regulatory role in mitochondrial function and fatty acid oxidation. In: Molecular and Cellular Proteomics. 2015 ; Vol. 14, No. 11. pp. 3056-3071.
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abstract = "The protein substrates of sirtuin 5-regulated lysine malonylation (Kmal) remain unknown, hindering its functional analysis. In this study, we carried out proteomic screening, which identified 4042 Kmal sites on 1426 proteins in mouse liver and 4943 Kmal sites on 1822 proteins in human fibroblasts. Increased malonyl-CoA levels in malonyl-CoA decarboxylase (MCD)-deficient cells induces Kmal levels in substrate proteins. We identified 461 Kmal sites showing more than a 2-fold increase in response to MCD deficiency as well as 1452 Kmal sites detected only in MCD−/− fibroblast but not MCD+/+ cells, suggesting a pathogenic role of Kmal in MCD deficiency. Cells with increased lysine malonylation displayed impaired mitochondrial function and fatty acid oxidation, suggesting that lysine malonylation plays a role in pathophysiology of malonic aciduria. Our study establishes an association between Kmal and a genetic disease and offers a rich resource for elucidating the contribution of the Kmal pathway and malonyl-CoA to cellular physiology and human diseases.",
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Proteomic and biochemical studies of lysine malonylation suggest its malonic aciduria-associated regulatory role in mitochondrial function and fatty acid oxidation. / Colak, G.; Pougovkina, O.; Dai, L.; Tan, M.; te Brinke, H.; Huang, H.; Wanders, R.J.; Locasale, J.W.; Lombard, D.B.; de Boer, V.C.J.; Zhao, Y.

In: Molecular and Cellular Proteomics, Vol. 14, No. 11, 2015, p. 3056-3071.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Proteomic and biochemical studies of lysine malonylation suggest its malonic aciduria-associated regulatory role in mitochondrial function and fatty acid oxidation

AU - Colak, G.

AU - Pougovkina, O.

AU - Dai, L.

AU - Tan, M.

AU - te Brinke, H.

AU - Huang, H.

AU - Wanders, R.J.

AU - Locasale, J.W.

AU - Lombard, D.B.

AU - de Boer, V.C.J.

AU - Zhao, Y.

PY - 2015

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N2 - The protein substrates of sirtuin 5-regulated lysine malonylation (Kmal) remain unknown, hindering its functional analysis. In this study, we carried out proteomic screening, which identified 4042 Kmal sites on 1426 proteins in mouse liver and 4943 Kmal sites on 1822 proteins in human fibroblasts. Increased malonyl-CoA levels in malonyl-CoA decarboxylase (MCD)-deficient cells induces Kmal levels in substrate proteins. We identified 461 Kmal sites showing more than a 2-fold increase in response to MCD deficiency as well as 1452 Kmal sites detected only in MCD−/− fibroblast but not MCD+/+ cells, suggesting a pathogenic role of Kmal in MCD deficiency. Cells with increased lysine malonylation displayed impaired mitochondrial function and fatty acid oxidation, suggesting that lysine malonylation plays a role in pathophysiology of malonic aciduria. Our study establishes an association between Kmal and a genetic disease and offers a rich resource for elucidating the contribution of the Kmal pathway and malonyl-CoA to cellular physiology and human diseases.

AB - The protein substrates of sirtuin 5-regulated lysine malonylation (Kmal) remain unknown, hindering its functional analysis. In this study, we carried out proteomic screening, which identified 4042 Kmal sites on 1426 proteins in mouse liver and 4943 Kmal sites on 1822 proteins in human fibroblasts. Increased malonyl-CoA levels in malonyl-CoA decarboxylase (MCD)-deficient cells induces Kmal levels in substrate proteins. We identified 461 Kmal sites showing more than a 2-fold increase in response to MCD deficiency as well as 1452 Kmal sites detected only in MCD−/− fibroblast but not MCD+/+ cells, suggesting a pathogenic role of Kmal in MCD deficiency. Cells with increased lysine malonylation displayed impaired mitochondrial function and fatty acid oxidation, suggesting that lysine malonylation plays a role in pathophysiology of malonic aciduria. Our study establishes an association between Kmal and a genetic disease and offers a rich resource for elucidating the contribution of the Kmal pathway and malonyl-CoA to cellular physiology and human diseases.

KW - Proteomic

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KW - mitochondrial function

KW - fatty acid oxydation

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DO - 10.1074/mcp.M115.048850

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