title: Metallothionein prevents cardiac pathological changes in diabetes by modulating nitration and inactivation of cardiac ATP synthase.
abstract: Mitochondrial ATP production is the main energy source for the cell. Diabetes reduces the efficient generation of ATP, possibly due to the inactivation of ATP synthase. However, the exact mechanism by which diabetes induces inactivation of ATP synthase remains unknown, as well as whether such inactivation has a role in the development of pathological abnormalities of the diabetic heart. To address these issues, we used cardiac metallothionein-transgenic (MT-TG) and wild-type (WT) mice with streptozotocin-induced diabetes, since we have demonstrated previously that diabetes-induced cardiac damage and remodeling were found in WT diabetic mice, but not in MT-TG diabetic mice. Immunohistochemical and biochemical assays were used to compare pathological and biochemical changes of the heart between MT-TG and WT diabetic mice, and a proteomic assay to evaluate ATP synthase expression and tyrosine nitration, with its activity. LC/MS analysis revealed that diabetes increased tyrosine nitration of the ATP synthase α subunit at Tyr(271), Tyr(311), and Tyr(476), and the β subunit at Tyr(269) and Tyr(508), and also significantly reduced ATP synthase activity by ~32%. These changes were not observed in MT-TG diabetic mice. Furthermore, parallel experiments with induced expression of cardiac MT by zinc supplementation in diabetic mice produced similar effects. These results suggest that MT can preserve ATP synthase activity in streptozotocin-induced diabetes, probably through the inhibition of ATP synthase nitration.
authors.affiliation: Chinese-American Research Institute for Diabetic Complications, Wenzhou Medical University, Zhejiang, P.R. China; School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, P.R. China.
authors.forename: Weitao
authors.initials: W
authors.lastname: Cong
authors.affiliation: Chinese-American Research Institute for Diabetic Complications, Wenzhou Medical University, Zhejiang, P.R. China; School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, P.R. China.
authors.forename: Ting
authors.initials: T
authors.lastname: Zhao
authors.affiliation: Chinese-American Research Institute for Diabetic Complications, Wenzhou Medical University, Zhejiang, P.R. China; School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, P.R. China.
authors.forename: Zhongxin
authors.initials: Z
authors.lastname: Zhu
authors.affiliation: Chinese-American Research Institute for Diabetic Complications, Wenzhou Medical University, Zhejiang, P.R. China; School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, P.R. China.
authors.forename: Binbin
authors.initials: B
authors.lastname: Huang
authors.affiliation: Laboratory of Gynecology and Obstetrics, People's Hospital of Wenzhou, Zhejiang, P.R. China.
authors.forename: Weide
authors.initials: W
authors.lastname: Ma
authors.affiliation: Department of Geriatric Medicine, The First Hospital of Jilin University, Changchun, P.R. China.
authors.forename: Yuehui
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Chinese-American Research Institute for Diabetic Complications, Wenzhou Medical University, Zhejiang, P.R. China; Kosair Children's Hospital Research Institute (KCHRI), Department of Pediatrics, University of Louisville School of Medicine, Louisville, KY, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Tan
authors.affiliation: Department of Pathology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, Canada.
authors.forename: Subrata
authors.initials: S
authors.lastname: Chakrabarti
authors.affiliation: Chinese-American Research Institute for Diabetic Complications, Wenzhou Medical University, Zhejiang, P.R. China; School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, P.R. China.
authors.forename: Xiaokun
authors.initials: X
authors.lastname: Li
authors.affiliation: Chinese-American Research Institute for Diabetic Complications, Wenzhou Medical University, Zhejiang, P.R. China; School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, P.R. China. Electronic address: Jin_litai@126.com.
authors.forename: Litai
authors.initials: L
authors.lastname: Jin
authors.affiliation: Chinese-American Research Institute for Diabetic Complications, Wenzhou Medical University, Zhejiang, P.R. China; Kosair Children's Hospital Research Institute (KCHRI), Department of Pediatrics, University of Louisville School of Medicine, Louisville, KY, USA. Electronic address: L0cai001@louisville.edu.
authors.forename: Lu
authors.initials: L
authors.lastname: Cai
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000473:pathology*; D019587:Dietary Supplements; D004789:Enzyme Activation; D008297:Male; D008668:Metallothionein / Q000235:genetics* / Q000378:metabolism; D008822:Mice, Transgenic; D025261:Mitochondrial Proton-Translocating ATPases / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D021122:Protein Subunits / Q000378:metabolism; D013311:Streptozocin; D013481:Superoxides / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism*; D015032:Zinc / Q000494:pharmacology
chemical_list: D021122:Protein Subunits; D013481:Superoxides; D014443:Tyrosine; D013311:Streptozocin; D008668:Metallothionein; D025261:Mitochondrial Proton-Translocating ATPases; D015032:Zinc
keywords: ATP synthase α subunit; ATP synthase β subunit; Diabetic cardiomyopathy; Metallothionein; Nitration