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Increased enzymatic glycosylation of mitochondrial proteins impairs mitochondrial function in cardiomyocytes
Author(s) -
Suarez Jorge,
Hu Yong,
Fricovsky Eduardo,
Wang Hong,
Scott Brian T,
Han Wenlong,
Dillmann Wolfgang H
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.856.10
Subject(s) - immunoprecipitation , protein subunit , mitochondrion , serine , glycosylation , chemistry , microbiology and biotechnology , enzyme , function (biology) , biochemistry , biology , gene
Increased nuclear protein O‐linked β‐N‐acetylglucosamine glycosylation (O‐GlcNAcylation) mediated by hyperglycemia contributes to cardiomyocyte dysfunction. However, whether mitochondrial (MITO) proteins are submitted to O‐GlcNAcylation or excessive O‐GlcNAcylation alters MITO function is unknown. Here, we investigated if MITO proteins are O‐GlcNAcylated and if increased O‐GlcNAcylation is linked to HG‐induced MITO dysfunction in neonatal rat cardiomyocytes. By immunoprecipitation, we found that MITO proteins, members of complexes of the respiratory chain, like subunit NDUFA9 of complex I, subunits core1 and core2 of complex III, and the MITO DNA encoded subunit I of complex IV (COX I) are O‐GlcNAcylated. By Mass Spectrometry, we identified that Serine 156 on NDUFA9 is O‐GlcNAcylated. HG treatment (30mM glucose) increases MITO protein O‐GlcNAcylation, including those of COX I and NDUFA9 which is reduced by expression of O‐GlcNAcase (GCA). Increased MITO O‐GlcNAcylation is associated with impaired activity of complex I, III and IV, and lower MITO calcium and cellular ATP content. Reducing O‐GlcNAcylation increased the activity of complex I, III and IV and MITO calcium and cellular ATP content returned to control levels. In conclusion, specific MITO proteins of cardiac myocytes are O‐GlcNAcylated and HG increases O‐GlcNAcylation of MITO proteins impairing MITO function. NIH Grant HL‐66917.