Reversal of mitochondrial proteomic loss in Type 1 diabetic heart with overexpression of phospholipid hydroperoxide glutathione peroxidase
| العنوان: | Reversal of mitochondrial proteomic loss in Type 1 diabetic heart with overexpression of phospholipid hydroperoxide glutathione peroxidase |
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| المؤلفون: | John M. Hollander, Cody E. Nichols, Dharendra Thapa, Erinne R. Dabkowski, Sara E. Lewis, Danielle L. Shepherd, Tara L. Croston, Rajaganapathi Jagannathan, Matthew J. Powell, Walter A. Baseler, Trust T. Razunguzwa, David M. Schnell |
| المصدر: | American Journal of Physiology-Regulatory, Integrative and Comparative Physiology. 304:R553-R565 |
| بيانات النشر: | American Physiological Society, 2013. |
| سنة النشر: | 2013 |
| مصطلحات موضوعية: | Male, Proteomics, medicine.medical_specialty, Diabetic Cardiomyopathies, Physiology, Mice, Transgenic, Oxidative phosphorylation, Mitochondrion, Biology, medicine.disease_cause, Gene Expression Regulation, Enzymologic, Mass Spectrometry, Mitochondria, Heart, Diabetes Mellitus, Experimental, Mice, chemistry.chemical_compound, Physiology (medical), Internal medicine, Diabetic cardiomyopathy, medicine, Animals, Phospholipid-hydroperoxide glutathione peroxidase, Inner mitochondrial membrane, Beta oxidation, Heart metabolism, Glutathione Peroxidase, Biological Transport, Phospholipid Hydroperoxide Glutathione Peroxidase, medicine.disease, Obesity, Diabetes and Energy Homeostasis, Oxidative Stress, Diabetes Mellitus, Type 1, Endocrinology, chemistry, Female, Lipid Peroxidation, Reactive Oxygen Species, Oxidative stress |
| الوصف: | Mitochondrial dysfunction is a contributor to diabetic cardiomyopathy. Previously, we observed proteomic decrements within the inner mitochondrial membrane (IMM) and matrix of diabetic cardiac interfibrillar mitochondria (IFM) correlating with dysfunctional mitochondrial protein import. The goal of this study was to determine whether overexpression of mitochondria phospholipid hydroperoxide glutathione peroxidase 4 (mPHGPx), an antioxidant enzyme capable of scavenging membrane-associated lipid peroxides in the IMM, could reverse proteomic alterations, dysfunctional protein import, and ultimately, mitochondrial dysfunction associated with the diabetic heart. MPHGPx transgenic mice and controls were made diabetic by multiple low-dose streptozotocin injections and examined after 5 wk of hyperglycemia. Five weeks after hyperglycemia onset, in vivo analysis of cardiac contractile function revealed decreased ejection fraction and fractional shortening in diabetic hearts that was reversed with mPHGPx overexpression. MPHGPx overexpression increased electron transport chain function while attenuating hydrogen peroxide production and lipid peroxidation in diabetic mPHGPx IFM. MPHGPx overexpression lessened proteomic loss observed in diabetic IFM. Posttranslational modifications, including oxidations and deamidations, were attenuated in diabetic IFM with mPHGPx overexpression. Mitochondrial protein import dysfunction in diabetic IFM was reversed with mPHGPx overexpression correlating with protein import constituent preservation. Ingenuity Pathway Analyses indicated that oxidative phosphorylation, tricarboxylic acid cycle, and fatty acid oxidation processes most influenced in diabetic IFM were preserved by mPHGPx overexpression. Specific mitochondrial networks preserved included complex I and II, mitochondrial ultrastructure, and mitochondrial protein import. These results indicate that mPHGPx overexpression can preserve the mitochondrial proteome and provide cardioprotective benefits to the diabetic heart. |
| تدمد: | 1522-1490 0363-6119 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::4aa944b3ea9184916503fb93d7870bdd https://doi.org/10.1152/ajpregu.00249.2012 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....4aa944b3ea9184916503fb93d7870bdd |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15221490 03636119 |
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