title: The mitochondrial O-linked N-acetylglucosamine transferase (mOGT) in the diabetic patient could be the initial trigger to develop Alzheimer disease.
abstract: Diabetes mellitus (DM) is considered a risk factor for the development of Alzheimer disease (AD); however, how DM favors evolution of AD is still insufficiently understood. Hyperglycemia in DM is associated to an increase in mitochondrial reactive oxygen species (ROS) generation, as well as damage of hippocampal cells, reflected by changes in morphological and mitochondrial functionality. Similar mitochondrial damage has been observed when amyloid beta (Aβ) accumulates in the brain of AD patients. In DM, the excess of glucose in the brain induces higher activity of the hexosamine biosynthesis pathway (HBP), it synthesizes UDP-N-acetylglucosamine (UDP-GlcNAc), which is used by O-linked N-acetylglucosamine transferase (OGT) to catalyze O-GlcNAcylation of numerous proteins. Although O-GlcNAcylation plays an important role in maintaining structure and cellular functionality, chronic activity of this pathway has been associated with insulin resistance and hyperglycemia-induced glucose toxicity. Three different forms of OGT are known: nucleocytoplasmic (ncOGT), short (sOGT), and mitochondrial (mOGT). Previous reports showed that overexpression of ncOGT is not toxic to the cell; in contrast, overexpression of mOGT is associated with cellular apoptosis. In this work, we suggest that hyperglycemia in the diabetic patient could induce greater expression and activity of mOGT, modifying the structure and functionality of mitochondria in hippocampal cells, accelerating neuronal damage, and favoring the start of AD. In consequence, mOGT activity could be a key point for AD development in patients with DM.
authors.affiliation: National Autonomous University of Mexico, Department of Biochemistry, Faculty of Medicine, Mexico.
authors.forename: Liliana
authors.initials: L
authors.lastname: Lozano
authors.affiliation: National Institute of Respiratory Diseases, "Ismael Cosío Villegas", Mexico.
authors.forename: Roberto
authors.initials: R
authors.lastname: Lara-Lemus
authors.affiliation: National Autonomous University of Mexico, Department of Biochemistry, Faculty of Medicine, Mexico.
authors.forename: Edgar
authors.initials: E
authors.lastname: Zenteno
authors.affiliation: National Institute of Respiratory Diseases, "Ismael Cosío Villegas", Mexico. Electronic address: nnooee@gmail.com.
authors.forename: Noé
authors.initials: N
authors.lastname: Alvarado-Vásquez
mesh_terms: D000544:Alzheimer Disease / Q000201:enzymology / Q000209:etiology* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D048909:Diabetes Complications / Q000097:blood / Q000150:complications / Q000201:enzymology* / Q000473:pathology; D006031:Glycosylation; D006624:Hippocampus / Q000201:enzymology* / Q000473:pathology; D006801:Humans; D008928:Mitochondria / Q000201:enzymology* / Q000473:pathology; D017351:N-Acetylglucosaminyltransferases / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D012307:Risk Factors
chemical_list: D016229:Amyloid beta-Peptides; D001786:Blood Glucose; D017351:N-Acetylglucosaminyltransferases
keywords: Alzheimer disease; Diabetes mellitus; Mitochondria; O-GlcNAcylation; O-glycosyl transferase