scholarly journals Excessive O - GlcNAcylation causes heart failure and sudden death

2020 ◽  
Author(s):  
Priya Umapathi ◽  
Partha S. Banerjee ◽  
Natasha E. Zachara ◽  
Neha Abrol ◽  
Qinchuan Wang ◽  
...  
Keyword(s):  
Heart Failure ◽  
Mouse Models ◽  
Complex I ◽  
Pressure Overload ◽  
Premature Death ◽  
List Type ◽  
Mitochondrial Complex ◽  
Pathological Hypertrophy ◽  
Complex I Activity ◽  
Genetic Mouse Models

AbstractBackgroundHeart failure is a leading cause of death worldwide and is associated with the rising prevalence of obesity, hypertension and diabetes. O-GlcNAcylation, a post-translational modification of intracellular proteins, serves as a potent transducer of cellular stress. Failing myocardium is marked by increased O-GlcNAcylation, but it is unknown if excessive O-GlcNAcylation contributes to cardiomyopathy and heart failure. The total levels of O-GlcNAcylation are determined by nutrient and metabolic flux, in addition to the net activity of two enzymes, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA).MethodsWe developed two new transgenic mouse models with myocardial overexpression of OGT and OGA to control O-GlcNAclyation independent of pathological stress.ResultsWe found that OGT transgenic hearts showed increased O-GlcNAcylation, and developed severe dilated cardiomyopathy, ventricular arrhythmias and premature death. In contrast, OGA transgenic hearts had O-GlcNAcylation and cardiac function similar to wild type littermate controls. However, OGA trangenic hearts were resistant to pathological stress induced by pressure overload and had attenuated myocardial O-GlcNAcylation levels, decreased pathological hypertrophy and improved systolic function. Interbreeding OGT with OGA transgenic mice rescued cardiomyopathy and premature death despite persistant elevation of myocardial OGT. Transcriptomic and functional studies revealed disrupted mitochondrial energetics with impairment of complex I activity in hearts from OGT transgenic mice. Complex I activity was rescued by OGA transgenic interbreeding, suggesting an important role for mitochondrial complex I in O-GlcNAc mediated cardiac pathology.ConclusionsOur data provide evidence that excessive O-GlcNAcylation causes cardiomyopathy, at least in part, due to defective energetics. Enhanced OGA activity is well tolerated and attenuation of O-GlcNAcylation is an effective therapy against pressure overload induced heart failure. Attenuation of excessive O-GlcNAcylation may represent a novel therapeutic approach for cardiomyopathy.Clinical PerspectiveWhat is new?Cardiomyopathy from diverse causes is marked by increased O-GlcNAcylation. Here we provide new genetic mouse models to control myocardial O-GlcNAcylation independent of pathological stress.Genetically increased myocardial O-GlcNAcylation causes progressive dilated cardiomyopathy and premature death, while genetic reduction of myocardial O-GlcNAcylation is protective against pathological hypertrophy caused by transaortic banding.Excessive myocardial O-GlcNAcylation decreases activity and expression of mitochondrial complex I.What are the clinical implications?Increased myocardial O-GlcNAcylation has been shown to be associated with a diverse range of clinical heart failure including aortic stenosis, hypertension, ischemia and diabetes.Using novel genetic mouse models we have provided new proof of concept data that excessive O-GlcNAcylation is sufficient to cause cardiomyopathy.We have shown myocardial over-expression of O-GlcNAcase, an enzyme that reverses O-GlcNAcylation, is well tolerated at baseline, and improves myocardial responses to pathological stress.Our findings suggest reversing excessive myocardial O-GlcNAcylation could benefit diverse etiologies of heart failure.

scholarly journals Excessive O -GlcNAcylation Causes Heart Failure and Sudden Death

Circulation ◽  
2021 ◽  
Vol 143 (17) ◽  
pp. 1687-1703
Author(s):  
Priya Umapathi ◽  
Olurotimi O. Mesubi ◽  
Partha S. Banerjee ◽  
Neha Abrol ◽  
Qinchuan Wang ◽  
...  
Keyword(s):  
Heart Failure ◽  
Transgenic Mice ◽  
Complex I ◽  
Metabolic Flux ◽  
Pressure Overload ◽  
Premature Death ◽  
Wild Type ◽  
Wild Type Littermate ◽  
Functional Studies ◽  
Complex I Activity

Background: Heart failure is a leading cause of death worldwide and is associated with the rising prevalence of obesity, hypertension, and diabetes. O -GlcNAcylation (the attachment of O -linked β-N-acetylglucosamine [ O -GlcNAc] moieties to cytoplasmic, nuclear, and mitochondrial proteins) is a posttranslational modification of intracellular proteins and serves as a metabolic rheostat for cellular stress. Total levels of O -GlcNAcylation are determined by nutrient and metabolic flux, in addition to the net activity of 2 enzymes: O -GlcNAc transferase (OGT) and O -GlcNAcase (OGA). Failing myocardium is marked by increased O -GlcNAcylation, but whether excessive O -GlcNAcylation contributes to cardiomyopathy and heart failure is unknown. Methods: We developed 2 new transgenic mouse models with myocardial overexpression of OGT and OGA to control O -GlcNAcylation independent of pathologic stress. Results: We found that OGT transgenic hearts showed increased O -GlcNAcylation and developed severe dilated cardiomyopathy, ventricular arrhythmias, and premature death. In contrast, OGA transgenic hearts had lower O -GlcNAcylation but identical cardiac function to wild-type littermate controls. OGA transgenic hearts were resistant to pathologic stress induced by pressure overload with attenuated myocardial O -GlcNAcylation levels after stress and decreased pathologic hypertrophy compared with wild-type controls. Interbreeding OGT with OGA transgenic mice rescued cardiomyopathy and premature death, despite persistent elevation of myocardial OGT. Transcriptomic and functional studies revealed disrupted mitochondrial energetics with impairment of complex I activity in hearts from OGT transgenic mice. Complex I activity was rescued by OGA transgenic interbreeding, suggesting an important role for mitochondrial complex I in O -GlcNAc–mediated cardiac pathology. Conclusions: Our data provide evidence that excessive O -GlcNAcylation causes cardiomyopathy, at least in part, attributable to defective energetics. Enhanced OGA activity is well tolerated and attenuation of O -GlcNAcylation is beneficial against pressure overload–induced pathologic remodeling and heart failure. These findings suggest that attenuation of excessive O -GlcNAcylation may represent a novel therapeutic approach for cardiomyopathy.

scholarly journals Differential effects of various genetic mouse models of the mechanistic target of rapamycin complex I inhibition on heart failure

GeroScience ◽  
2019 ◽  
Vol 41 (6) ◽  
pp. 847-860 ◽  
Author(s):  
Dao-Fu Dai ◽  
Yonggang Liu ◽  
Nathan Basisty ◽  
Pabalu Karunadharma ◽  
Somasish G. Dastidar ◽  
...  
Keyword(s):  
Heart Failure ◽  
Mouse Models ◽  
Complex I ◽  
Target Of Rapamycin ◽  
Differential Effects ◽  
Mechanistic Target Of Rapamycin ◽  
Genetic Mouse Models

Pressure overload induced heart failure may be due to impaired respiratory capacity and a defect in complex I

2013 ◽  
Vol 61 (S 01) ◽  
Author(s):  
M Schwarzer ◽  
M Osterholt ◽  
A Schrepper ◽  
PA Amorim ◽  
T Doenst
Keyword(s):  
Heart Failure ◽  
Complex I ◽  
Pressure Overload ◽  
Respiratory Capacity

Mutants of Chlamydomonas reinhardtii Deficient in Mitochondrial Complex I: Characterization of Two Mutations Affecting the nd1 Coding Sequence

Genetics ◽  
2001 ◽  
Vol 158 (3) ◽  
pp. 1051-1060
Author(s):  
Claire Remacle ◽  
Denis Baurain ◽  
Pierre Cardol ◽  
René F Matagne
Keyword(s):  
Mitochondrial Genome ◽  
Chlamydomonas Reinhardtii ◽  
Complex I ◽  
Slow Growth ◽  
Nadh:Ubiquinone Oxidoreductase ◽  
Sequencing Analysis ◽  
Mitochondrial Complex ◽  
Genetical Analysis ◽  
Complex I Activity

Abstract The mitochondrial rotenone-sensitive NADH:ubiquinone oxidoreductase (complex I) comprises more than 30 subunits, the majority of which are encoded by the nucleus. In Chlamydomonas reinhardtii, only five components of complex I are coded for by mitochondrial genes. Three mutants deprived of complex I activity and displaying slow growth in the dark were isolated after mutagenic treatment with acriflavine. A genetical analysis demonstrated that two mutations (dum20 and dum25) affect the mitochondrial genome whereas the third mutation (dn26) is of nuclear origin. Recombinational analyses showed that dum20 and dum25 are closely linked on the genetic map of the mitochondrial genome and could affect the nd1 gene. A sequencing analysis confirmed this conclusion: dum20 is a deletion of one T at codon 243 of nd1; dum25 corresponds to a 6-bp deletion that eliminates two amino acids located in a very conserved hydrophilic segment of the protein.

CFM6 is an Essential CRM Protein Required for the Splicing of nad5 Transcript in Arabidopsis Mitochondria

2021 ◽  
Author(s):  
Wei-Chih Lin ◽  
Ya-Huei Chen ◽  
Shin-Yuan Gu ◽  
Hwei-Ling Shen ◽  
Kai-Chau Huang ◽  
...  
Keyword(s):  
Complex I ◽  
Mitochondrial Complex I ◽  
Mitochondrial Complex ◽  
High Accumulation ◽  
Stunted Growth ◽  
Growth Defects ◽  
Group I ◽  
Or Genes ◽  
Complex I Activity ◽  
Intron 4

Abstract Plant CRM domain-containing proteins are capable of binding RNA to facilitate the splicing of group I or II introns in chloroplasts, but their functions in mitochondria are less clear. In the present study, Arabidopsis thaliana CFM6, a protein with a single CRM domain, was expressed in most plant tissues, particularly in flower tissues, and restricted to mitochondria. Mutation of CFM6 causes severe growth defects, including stunted growth, curled leaves, delayed embryogenesis, and pollen development. CFM6 functions specifically in the splicing of group II intron 4 of nad5, which encodes a subunit of mitochondrial complex I, as evidenced by the loss of nad5 intron 4 splicing and high accumulation of its pretranscripts in cfm6 mutants. The phenotypic and splicing defects of cfm6 were rescued in transgenic plants overexpressing 35S::CFM6-YFP. Splicing failure in cfm6 also led to the loss of complex I activity and to its improper assembly. Moreover, dysfunction of complex I induced the expression of proteins or genes involved in alternative respiratory pathways in cfm6. Collectively, CFM6, a previously uncharacterized CRM domain-containing protein, is specifically involved in the cis-splicing of nad5 intron 4 and plays a pivotal role in mitochondrial complex I biogenesis and normal plant growth.

scholarly journals Downregulation of DJ-1 Fails to Protect Mitochondrial Complex I Subunit NDUFS3 in the Testes and Contributes to the Asthenozoospermia

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Yupeng Wang ◽  
Yi Sun ◽  
Xin Zhao ◽  
Renpei Yuan ◽  
Hui Jiang ◽  
...  
Keyword(s):  
Male Infertility ◽  
Complex I ◽  
Mitochondrial Protein ◽  
Protein Product ◽  
Mitochondrial Activity ◽  
Mitochondrial Complex ◽  
Specific Mechanism ◽  
Nicotinamide Adenine Dinucleotide Dehydrogenase ◽  
Complex I Activity ◽  
Mitochondria Complex I

Asthenozoospermia (AS), an important cause of male infertility, is characterized by reduced sperm motility. Among the aetiologies of AS, inflammation seems to be the main cause. DJ-1, a conserved protein product of thePARK7gene, is associated with male infertility and plays a role in oxidative stress and inflammation. Although our previous studies showed that a reduction in DJ-1 was accompanied by mitochondrial dysfunction in the sperm of patients with AS, the specific mechanism underlying this association remained unclear. In this study, we found that compared to the patients without AS, the expression of mitochondrial protein nicotinamide adenine dinucleotide dehydrogenase (ubiquinone) Fe-S protein 3 (NDUFS3) was also significantly decreased in the sperm of patients with AS. Similarly, decreased expression of DJ-1 and NDUFS3 and reduced mitochondria complex I activity were evident in a rat model of AS. Moreover, we showed that the interaction between DJ-1 and NDUFS3 in rat testes was weakened by ORN treatment. These results suggest that the impaired mitochondrial activity could be due to the broken interaction between DJ-1 and NDUFS3 and that downregulation of DJ-1 in sperm and testes contributes to AS pathogenesis.

Synthesis and Mitochondrial Complex I Activity of Annonaceous Trans and Cis Solamins Precursors

2004 ◽  
Vol 1 (4) ◽  
pp. 316-322 ◽  
Author(s):  
Julie Defretin ◽  
Christophe Gleye ◽  
Diego Cortes ◽  
Xavier Franck ◽  
Reynald Hocquemiller ◽  
...  
Keyword(s):  
Complex I ◽  
Mitochondrial Complex I ◽  
Mitochondrial Complex ◽  
Complex I Activity
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