Altering O-linked β-N-acetylglucosamine cycling disrupts mitochondrial function.
Mitochondrial impairment is commonly found in many diseases such as diabetes, cancer, and Alzheimer disease. We demonstrate that the enzymes responsible for the addition or removal of the O-GlcNAc modification, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), respectively, are critical regulators of mitochondrial function. Using a SILAC (stable isotope labeling of amino acids in cell culture)-based proteomics screen, we quantified the changes in mitochondrial protein expression in OGT- and OGA-overexpressing cells. Strikingly, overexpression of OGT or OGA showed significant decreases in mitochondria-localized proteins involved in the respiratory chain and the tricarboxylic acid cycle. Furthermore, mitochondrial morphology was altered in these cells. Both cellular respiration and glycolysis were reduced in OGT/OGA-overexpressing cells. These data demonstrate that alterations in O-GlcNAc cycling profoundly affect energy and metabolite production.
From the Department of Biochemistry and Molecular Biology.
Ee Phie
EP
Tan
From the Department of Biochemistry and Molecular Biology.
Maria T
MT
Villar
Department of Neurology, and.
Lezi
L
E
Department of Neurology, and.
Jianghua
J
Lu
Department of Neurology, and.
J Eva
JE
Selfridge
From the Department of Biochemistry and Molecular Biology.
Antonio
A
Artigues
From the Department of Biochemistry and Molecular Biology, Department of Neurology, and University of Kansas Alzheimer's Disease Center, University of Kansas Medical Center, Kansas City, Kansas 64108.
Russell H
RH
Swerdlow
From the Department of Biochemistry and Molecular Biology, University of Kansas Alzheimer's Disease Center, University of Kansas Medical Center, Kansas City, Kansas 64108 University of Kansas Cancer Center, cslawson@kumc.edu.
Chad
C
Slawson
D000117:Acetylglucosamine / Q000378:metabolism*; D045744:Cell Line, Tumor; D002952:Citric Acid Cycle; D004579:Electron Transport; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006019:Glycolysis; D006801:Humans; D015151:Immunoblotting; D013058:Mass Spectrometry; D008854:Microscopy, Electron; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D024101:Mitochondrial Proteins / Q000378:metabolism*; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics / Q000378:metabolism; D040901:Proteomics / Q000379:methods; D001619:beta-N-Acetylhexosaminidases / Q000235:genetics / Q000378:metabolism
D024101:Mitochondrial Proteins; D017351:N-Acetylglucosaminyltransferases; C063057:UDP-N-acetylglucosamine-peptide beta-N-acetylglucosaminyltransferase; C110628:hexosaminidase C; D001619:beta-N-Acetylhexosaminidases; D000117:Acetylglucosamine
Glycobiology; Glycosylation; Mass Spectrometry (MS); Metabolomics; Mitochondria; Mitochondrial Metabolism