The mitochondrial O-linked N-acetylglucosamine transferase (mOGT) in the diabetic patient could be the initial trigger to develop Alzheimer disease

Lozano, Liliana; Lara-Lemus, Roberto; Zenteno, Edgar; Alvarado-Vásquez, Noé

doi:10.1016/j.exger.2014.08.008

Cited by 21 publications

(12 citation statements)

References 87 publications

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“…However, the change in membrane potential suggests that defects in membrane structure, perhaps by altered or imbalanced incorporation of fatty acids into the mitochondrial membrane may be involved. Gluctoxicity37, or lipotoxicity due to lipid species such as saturated free fatty acids38 or ceramides39 also may be mediators of mitochondrial damage in this disease. Thus, it is possible that the excessive intracellular carbohydrates or lipids in this disease may lead to the mitchondrial dysfunction.…”

Section: Discussionmentioning

confidence: 99%

Hepatic mitochondrial dysfunction is a feature of Glycogen Storage Disease Type Ia (GSDIa)

Farah

Sinha

et al. 2017

Sci Rep

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Glycogen storage disease type Ia (GSDIa, von Gierke disease) is the most common glycogen storage disorder. It is caused by the deficiency of glucose-6-phosphatase, an enzyme which catalyses the final step of gluconeogenesis and glycogenolysis. Clinically, GSDIa is characterized by fasting hypoglycaemia and hepatic glycogen and triglyceride overaccumulation. The latter leads to steatohepatitis, cirrhosis, and the formation of hepatic adenomas and carcinomas. Currently, little is known about the function of various organelles and their impact on metabolism in GSDIa. Accordingly, we investigated mitochondrial function in cell culture and mouse models of GSDIa. We found impairments in oxidative phosphorylation and changes in TCA cycle metabolites, as well as decreased mitochondrial membrane potential and deranged mitochondrial ultra-structure in these model systems. Mitochondrial content also was decreased, likely secondary to decreased mitochondrial biogenesis. These deleterious effects culminated in the activation of the mitochondrial apoptosis pathway. Taken together, our results demonstrate a role for mitochondrial dysfunction in the pathogenesis of GSDIa, and identify a new potential target for the treatment of this disease. They also provide new insight into the role of carbohydrate overload on mitochondrial function in other hepatic diseases, such as non-alcoholic fatty liver disease.

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Section: Discussionmentioning

confidence: 99%

Hepatic mitochondrial dysfunction is a feature of Glycogen Storage Disease Type Ia (GSDIa)

Farah

Sinha

et al. 2017

Sci Rep

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“…Furthermore, a recent study revealed that the levels of OGT and OGA are dramatically altered in mitochondria from diabetic mice hearts with significant mislocalization of OGT in the mitochondrial matrix and reduced interaction of OGT with complex IV (22). In addition, deregulation of O-GlcNAcylation has also been implicated in the pathology of neurodegenerative diseases, in particular in Alzheimer's disease (49), and underlies the pathology of both diabetes mellitus and Alzheimer's disease (50). In line with this concept, our data suggest that endogenous pools of OGT isoforms are critical for regulating essential cell functions and that alterations in the expression levels of OGT, whether induced by oxidative stress or disease, can alter the bioenergetics status and cell survival under stress conditions.…”

Section: Spotmentioning

confidence: 99%

Mitochondrial O-GlcNAc Transferase (mOGT) Regulates Mitochondrial Structure, Function, and Survival in HeLa Cells

Sacoman

Dagda

Burnham-Marusich

et al. 2017

Journal of Biological Chemistry

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Edited by Gerald W. HartO-Linked N-acetylglucosamine transferase (OGT) catalyzes O-GlcNAcylation of target proteins and regulates numerous biological processes. OGT is encoded by a single gene that yields nucleocytosolic and mitochondrial isoforms. To date, the role of the mitochondrial isoform of OGT (mOGT) remains largely unknown. Using high throughput proteomics, we identified 84 candidate mitochondrial glycoproteins, of which 44 are novel. Notably, two of the candidate glycoproteins identified (cytochrome oxidase 2 (COX2) and NADH:ubiquinone oxidoreductase core subunit 4 (MT-ND4)) are encoded by mitochondrial DNA. Using siRNA in HeLa cells, we found that reducing endogenous mOGT expression leads to alterations in mitochondrial structure and function, including Drp1-dependent mitochondrial fragmentation, reduction in mitochondrial membrane potential, and a significant loss of mitochondrial content in the absence of mitochondrial ROS. These defects are associated with a compensatory increase in oxidative phosphorylation per mitochondrion. mOGT is also critical for cell survival; siRNA-mediated knockdown of endogenous mOGT protected cells against toxicity mediated by rotenone, a complex I inhibitor. Conversely, reduced expression of both nucleocytoplasmic (ncOGT) and mitochondrial (mOGT) OGT isoforms is associated with increased mitochondrial respiration and elevated glycolysis, suggesting that ncOGT is a negative regulator of cellular bioenergetics. Last, we determined that mOGT is probably involved in the glycosylation of a restricted set of mitochondrial targets. We identified four proteins implicated in mitochondrial biogenesis and metabolism regulation as candidate substrates of mOGT, including leucine-rich PPR-containing protein and mitochondrial aconitate hydratase. Our findings suggest that mOGT is catalytically active in vivo and supports mitochondrial structure, health, and survival, whereas ncOGT predominantly regulates cellular bioenergetics.

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“…However, many other types of PTM are also known to be associated with various neurodegenerative conditions. These PTMs, not discussed in this review, include: adduct formation with DNA, lipids and proteins (de la Monte and Tong, 2014; Sultana et al, 2013), carbonylation (Ergin et al, 2013; Oikawa et al, 2014; Sultana et al, 2013), glycation (e.g., advanced glycation end products) (Byun et al, 2012; Choi et al, 2014), methylation (Pattaroni and Jacob, 2013; Peña-Altamira et al, 2013; Tradewell et al, 2012), N-linked glycosylation with Asn (Gonçalves et al, 2015; Mkhikian et al, 2011; Schedin-Weiss et al, 2014), O-linked glycosylation with Ser or Thr (Karababa et al, 2014; Lozano et al, 2014; Tan et al, 2014; Zhu et al, 2014), sumoylation (Gebriel et al, 2014; ; Nistico et al, 2014; Shahpasandzadeh et al, 2014), ubiquitination (Bishop et al, 2014; Gebriel et al, 2014; Karababa et al, 2014; Nistico et al, 2014; Schmid et al, 2013), etc.…”

Section: Consequences Of Increased Nitroxidative Stressmentioning

confidence: 99%

Mitochondrial dysfunction and cell death in neurodegenerative diseases through nitroxidative stress

et al. 2016

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Mitochondria are important for providing cellular energy ATP through the oxidative phosphorylation pathway. They are also critical in regulating many cellular functions including the fatty acid oxidation, the metabolism of glutamate and urea, the anti-oxidant defense, and the apoptosis pathway. Mitochondria are an important source of reactive oxygen species leaked from the electron transport chain while they are susceptible to oxidative damage, leading to mitochondrial dysfunction and tissue injury. In fact, impaired mitochondrial function is commonly observed in many types of neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, alcoholic dementia, brain ischemia-reperfusion related injury, and others, although many of these neurological disorders have unique etiological factors. Mitochondrial dysfunction under many pathological conditions is likely to be promoted by increased nitroxidative stress, which can stimulate post-translational modifications (PTMs) of mitochondrial proteins and/or oxidative damage to mitochondrial DNA and lipids. Furthermore, recent studies have demonstrated that various antioxidants, including naturally occurring flavonoids and polyphenols as well as synthetic compounds, can block the formation of reactive oxygen and/or nitrogen species, and thus ultimately prevent the PTMs of many proteins with improved disease conditions. Therefore, the present review is aimed to describe the recent research developments in the molecular mechanisms for mitochondrial dysfunction and tissue injury in neurodegenerative diseases and discuss translational research opportunities.

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The mitochondrial O-linked N-acetylglucosamine transferase (mOGT) in the diabetic patient could be the initial trigger to develop Alzheimer disease

Cited by 21 publications

References 87 publications

Hepatic mitochondrial dysfunction is a feature of Glycogen Storage Disease Type Ia (GSDIa)

Hepatic mitochondrial dysfunction is a feature of Glycogen Storage Disease Type Ia (GSDIa)

Mitochondrial O-GlcNAc Transferase (mOGT) Regulates Mitochondrial Structure, Function, and Survival in HeLa Cells

Mitochondrial dysfunction and cell death in neurodegenerative diseases through nitroxidative stress

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