Metallothionein prevents cardiac pathological changes in diabetes by modulating nitration and inactivation of cardiac ATP synthase

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• 作者：Weitao Cong^a ; ^b ; ¹ ; Ting Zhao^a ; ^b ; ¹ ; Zhongxin Zhu^a ; ^b ; Binbin Huang^a ; ^b ; Weide Ma^c ; Yuehui Wang^d ; Yi Tan^a ; ^e ; Subrata Chakrabarti^f ; Xiaokun Li^a ; ^b ; Litai Jin^a ; ^b ; ^{Jin_litai@126.com" class="auth_mail} ; Lu Cai^a ; ^e ; ^{L0cai001@louisville.edu" class="auth_mail}
• 关键词：ATP synthase 伪 subunit ; ATP synthase 尾 subunit ; Metallothionein ; Nitration ; Diabetic cardiomyopathy
• 刊名：Journal of Nutritional Biochemistry
• 出版年：April, 2014
• 年：2014
• 卷：25
• 期：4
• 页码：463-474
• 全文大小：3606 K

文摘

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 伪 subunit at Tyr²⁷¹, Tyr³¹¹, and Tyr⁴⁷⁶, and the 尾 subunit at Tyr²⁶⁹ and Tyr⁵⁰⁸, 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.