Proteomic and Biochemical Studies of Lysine Malonylation Suggest Its Malonic Aciduria-associated Regulatory Role in Mitochondrial Function and Fatty Acid Oxidation.

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Colak, G; Pougovkina, O; Dai, L; Tan, M; Te Brinke, H; Huang, H; Cheng, Z; Park, J; Wan, X; Liu, X; Yue, WW; Wanders, RJA; Locasale, JW; Lombard, DB; de Boer, VCJ; Zhao, Y

Published Date

  • November 2015

Published In

Volume / Issue

  • 14 / 11

Start / End Page

  • 3056 - 3071

PubMed ID

  • 26320211

Pubmed Central ID

  • 26320211

Electronic International Standard Serial Number (EISSN)

  • 1535-9484

International Standard Serial Number (ISSN)

  • 1535-9476

Digital Object Identifier (DOI)

  • 10.1074/mcp.M115.048850

Language

  • eng