Proteomic and Biochemical Studies of Lysine Malonylation Suggest Its Malonic Aciduria-associated Regulatory Role in Mitochondrial Function and Fatty Acid Oxidation
Year: 2015
Type: article
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.
Source: Molecular & Cellular Proteomics
Institutions: University of Chicago, Chinese Academy of Sciences, Shanghai Institute of Materia Medica, State Key Laboratory of Drug Research, University of Michigan, Cornell University, University of Oxford, Amsterdam UMC Location University of Amsterdam, Emma Kinderziekenhuis, University of Amsterdam
Language: English
Subfield: Clinical Biochemistry
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $3,430
Funders: Foundation for the National Institutes of Health, Natural Science Foundation of Jilin Province, Wellcome Trust, National Natural Science Foundation of China, Nederlandse Organisatie voor Wetenschappelijk Onderzoek, National Science and Technology Major Project, National Institutes of Health, National Key Research and Development Program of China, National Institute on Aging, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases
Awards: Understanding metabolic flux and the control of mammalian cell growth, A UK Hub to Catalyse Open Target Discovery., G204038924, G2217677092, G223462343, Mechanisms of tumor suppression by the chromatin deacetylase SIRT6, G2404719718, A UK Hub to Catalyse Open Target Discovery., G3000354638, G3102874822, G3509083583, G3682436033, G4229926161, G440280687, Proteome Characterization Center: A Genoproteomics Pipeline for Cancer Biomarkers, G5461601197, Regulation of one carbon metabolism and epigenetics by SIRT5, G629746227, G6608671334, G6670678456, G8173436950, Biochemistry of lysine crotonylation pathway, G8630103610, G891906045, G9000138263, Michigan Diabetes Research Center (MDRC), Career Training in the Biology of Aging, G934208794, G9463270
OpenAlex ID: W2119861196