O-GlcNAcylation of 8-Oxoguanine DNA Glycosylase (Ogg1) Impairs Oxidative Mitochondrial DNA Lesion Repair in Diabetic Hearts.
mtDNA damage in cardiac myocytes resulting from increased oxidative stress is emerging as an important factor in the pathogenesis of diabetic cardiomyopathy. A prevalent lesion that occurs in mtDNA damage is the formation of 8-hydroxy-2'-deoxyguanosine (8-OHdG), which can cause mutations when not repaired properly by 8-oxoguanine DNA glycosylase (Ogg1). Although the mtDNA repair machinery has been described in cardiac myocytes, the regulation of this repair has been incompletely investigated. Here we report that the hearts of type 1 diabetic mice, despite having increased Ogg1 protein levels, had significantly lower Ogg1 activity than the hearts of control, non-type 1 diabetic mice. In diabetic hearts, we further observed increased levels of 8-OHdG and an increased amount of mtDNA damage. Interestingly, Ogg1 was found to be highly O-GlcNAcylated in diabetic mice compared with controls. In vitro experiments demonstrated that O-GlcNAcylation inhibits Ogg1 activity, which could explain the mtDNA lesion accumulation observed in vivo Reducing Ogg1 O-GlcNAcylation in vivo by introducing a dominant negative O-GlcNAc transferase mutant (F460A) restored Ogg1 enzymatic activity and, consequently, reduced 8-OHdG and mtDNA damage despite the adverse hyperglycemic milieu. Taken together, our results implicate hyperglycemia-induced O-GlcNAcylation of Ogg1 in increased mtDNA damage and, therefore, provide a new plausible biochemical mechanism for diabetic cardiomyopathy.
From the Department of Medicine, University of California, San Diego, La Jolla, California 92093-0671 and fcividini@ucsd.edu.
Federico
F
Cividini
From the Department of Medicine, University of California, San Diego, La Jolla, California 92093-0671 and.
Brian T
BT
Scott
From the Department of Medicine, University of California, San Diego, La Jolla, California 92093-0671 and.
Anzhi
A
Dai
From the Department of Medicine, University of California, San Diego, La Jolla, California 92093-0671 and.
Wenlong
W
Han
From the Department of Medicine, University of California, San Diego, La Jolla, California 92093-0671 and.
Jorge
J
Suarez
the Department of Pharmacology, Instituto Nacional de Cardiología, Juan Badiano 41, Barrio Belisario Domínguez Secc XVI, 14080 Tlalpan, DF, Mexico.
Julieta
J
Diaz-Juarez
From the Department of Medicine, University of California, San Diego, La Jolla, California 92093-0671 and.
Tanja
T
Diemer
From the Department of Medicine, University of California, San Diego, La Jolla, California 92093-0671 and.
Darren E
DE
Casteel
From the Department of Medicine, University of California, San Diego, La Jolla, California 92093-0671 and wdillmann@ucsd.edu.
Wolfgang H
WH
Dillmann
D019943:Amino Acid Substitution; D000818:Animals; D004249:DNA Damage; D045647:DNA Glycosylases / Q000235:genetics / Q000378:metabolism*; D004272:DNA, Mitochondrial / Q000235:genetics / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D058065:Diabetic Cardiomyopathies / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006943:Hyperglycemia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008929:Mitochondria, Heart / Q000235:genetics / Q000378:metabolism*; D020125:Mutation, Missense; D032383:Myocytes, Cardiac / Q000378:metabolism*
D004272:DNA, Mitochondrial; D045647:DNA Glycosylases; C485990:Ogg1 protein, mouse
8-oxoguanine glycosylase (OGG1); cardiomyopathy; mtDNA; O-linked N-acetylglucosamine (O-GlcNAc); oxidative stress; type 1 diabetes