Altering O-Linked β-N-Acetylglucosamine Cycling Disrupts Mitochondrial Function

Tan, Ee Phie; Villar, María T.; Lezi, E; Lu, Jianghua; Selfridge, J. Eva; Artigues, Antonio; Swerdlow, Russell H.; Slawson, Chad

doi:10.1074/jbc.m113.525790

Cited by 85 publications

(78 citation statements)

References 28 publications

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“…However, the functional changes can potentially be attributed to alterations of mitochondrial protein abundance (12). In our study, acute TMG treatment of rats caused an overall increase in O-GlcNAcylation without changing the protein abundance, providing an excellent model for a systematic investigation of O-GlcNAc modulation of cardiac mitochondrial function.…”

Section: Discussionmentioning

confidence: 88%

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O-GlcNAcomic Profiling Identifies Widespread O-Linked β-N-Acetylglucosamine Modification (O-GlcNAcylation) in Oxidative Phosphorylation System Regulating Cardiac Mitochondrial Function

Ma¹,

Liu

Wei

et al. 2015

Journal of Biological Chemistry

100

127

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Background: Mitochondrial protein O-GlcNAcylation is not well understood.Results: Eighty eight mitochondrial proteins, involved in diverse pathways, are O-GlcNAcylated, and an overall increased O-GlcNAcylation leads to altered mitochondrial function. Conclusion: O-GlcNAcylation is on many mitochondrial proteins within the oxidative phosphorylation system, modulating cardiac mitochondrial function. Significance: O-GlcNAc cycles on many proteins within mitochondria, leading to altered function.

show abstract

Section: Discussionmentioning

confidence: 88%

“…Adenovirus-mediated overexpression of nucleocytoplasmic form of OGT and/or O-GlcNAcase provides some insights into the protein O-GlcNAcylation-related mitochondrial functions (11,12). However, the functional changes can potentially be attributed to alterations of mitochondrial protein abundance (12).…”

Section: Discussionmentioning

confidence: 99%

O-GlcNAcomic Profiling Identifies Widespread O-Linked β-N-Acetylglucosamine Modification (O-GlcNAcylation) in Oxidative Phosphorylation System Regulating Cardiac Mitochondrial Function

Ma¹,

Liu

Wei

et al. 2015

Journal of Biological Chemistry

100

127

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“…We speculate that mtDNA depletion could disorganize mitochondrial membranes and therefore disrupt glycosylation processes. Conversely, glycosylation abnormalities are known to affect mitochondrial function (Tan et al 2014). Further experiments are necessary to study the interplay among Twinkle mutations, mtDNA depletion, and glycosylation abnormalities.…”

Section: Discussionmentioning

confidence: 99%

Abnormal Glycosylation Profile and High Alpha-Fetoprotein in a Patient with Twinkle Variants

et al. 2016

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The C10orf2 gene encodes Twinkle, a protein involved in mitochondrial DNA (mtDNA) replication. Twinkle mutations cause mtDNA deletion or depletion and are associated with a large spectrum of clinical symptoms including dominant progressive external ophthalmoplegia (adPEO), infantile-onset spinocerebellar ataxia (IOSCA), and early-onset encephalopathy. The diagnosis remains difficult because of the wide range of symptoms and lack of association with specific metabolic changes. We report herein a child with early-onset encephalopathy, unusual abnormal movements, deafness, and axonal neuropathy. All laboratory investigations were normal with the exceptions of high alpha-fetoprotein levels and an abnormal glycosylation profile. These abnormal parameters resulted in misdiagnosis as a previously unidentified congenital disorder of glycosylation (CDG) type I syndrome. Whole exome sequencing revealed two point mutations in C10orf2 that were confirmed by Sanger sequencing; neither had been previously reported. This report enlarges the clinical phenotype of Twinkle mutations and suggests that an abnormal glycosylation profile suggestive of CDG type I associated with high blood alpha-fetoprotein levels without obvious cause should prompt Twinkle sequencing.

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“…Hu et al reported the modification of mitochondrial electron chain complexes by O-GlcNAc, which affected activities of complexes I, II, and IV (18). Altering O-GlcNAc levels by overexpression of cytoplasmic OGT or OGA had significant effects on mitochondrial function and mitochondrion-related protein expression (19). The existence of a mitochondrial isoform of OGT suggests that O-GlcNAcylation occurs within the mitochondria and on mito-specific proteins (20,21).…”

mentioning

confidence: 99%

Diabetes-associated dysregulation of O -GlcNAcylation in rat cardiac mitochondria

Banerjee¹,

Ma²,

Hart³

2015

Proc. Natl. Acad. Sci. U.S.A.

178

181

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Elevated mitochondrial O-GlcNAcylation caused by hyperglycemia, as occurs in diabetes, significantly contributes to mitochondrial dysfunction and to diabetic cardiomyopathy. However, little is known about the enzymology of mitochondrial O-GlcNAcylation. Herein, we investigated the enzymes responsible for cycling O-GlcNAc on mitochondrial proteins and studied the mitochondrial transport of UDP-GlcNAc. Analyses of purified rat heart mitochondria from normal and streptozocin-treated diabetic rats show increased mitochondrial O-GlcNAc transferase (OGT) and a concomitant decrease in the mito-specific O-GlcNAcase (OGA). Strikingly, OGT is mislocalized in cardiac mitochondria from diabetic rats. Interaction of OGT and complex IV observed in normal rat heart mitochondria is visibly reduced in diabetic samples, where OGT is mislocalized to the matrix. Live cell OGA activity assays establish the presence of O-GlcNAcase within the mitochondria. Furthermore, we establish that the inner mitochondrial membrane transporter, pyrimidine nucleotide carrier, transports UDP-GlcNAc from the cytosol to the inside of the mitochondria. Knockdown of this transporter substantially lowers mitochondrial O-GlcNAcylation. Inhibition of OGT or OGA activity within neonatal rat cardiomyocytes significantly affects energy production, mitochondrial membrane potential, and mitochondrial oxygen consumption. These data suggest that cardiac mitochondria not only have robust O-GlcNAc cycling, but also that dysregulation of O-GlcNAcylation likely plays a key role in mitochondrial dysfunction associated with diabetes.

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Altering O-Linked β-N-Acetylglucosamine Cycling Disrupts Mitochondrial Function

Cited by 85 publications

References 28 publications

O-GlcNAcomic Profiling Identifies Widespread O-Linked β-N-Acetylglucosamine Modification (O-GlcNAcylation) in Oxidative Phosphorylation System Regulating Cardiac Mitochondrial Function

O-GlcNAcomic Profiling Identifies Widespread O-Linked β-N-Acetylglucosamine Modification (O-GlcNAcylation) in Oxidative Phosphorylation System Regulating Cardiac Mitochondrial Function

Abnormal Glycosylation Profile and High Alpha-Fetoprotein in a Patient with Twinkle Variants

Diabetes-associated dysregulation of O -GlcNAcylation in rat cardiac mitochondria

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