title: Mitochondrial Calpain-1 Disrupts ATP Synthase and Induces Superoxide Generation in Type 1 Diabetic Hearts: A Novel Mechanism Contributing to Diabetic Cardiomyopathy.
abstract: Calpain plays a critical role in cardiomyopathic changes in type 1 diabetes (T1D). This study investigated how calpain regulates mitochondrial reactive oxygen species (ROS) generation in the development of diabetic cardiomyopathy. T1D was induced in transgenic mice overexpressing calpastatin, in mice with cardiomyocyte-specific capn4 deletion, or in their wild-type littermates by injection of streptozotocin. Calpain-1 protein and activity in mitochondria were elevated in diabetic mouse hearts. The increased mitochondrial calpain-1 was associated with an increase in mitochondrial ROS generation and oxidative damage and a reduction in ATP synthase-α (ATP5A1) protein and ATP synthase activity. Genetic inhibition of calpain or upregulation of ATP5A1 increased ATP5A1 and ATP synthase activity, prevented mitochondrial ROS generation and oxidative damage, and reduced cardiomyopathic changes in diabetic mice. High glucose concentration induced ATP synthase disruption, mitochondrial superoxide generation, and cell death in cardiomyocytes, all of which were prevented by overexpression of mitochondria-targeted calpastatin or ATP5A1. Moreover, upregulation of calpain-1 specifically in mitochondria induced the cleavage of ATP5A1, superoxide generation, and apoptosis in cardiomyocytes. In summary, calpain-1 accumulation in mitochondria disrupts ATP synthase and induces ROS generation, which promotes diabetic cardiomyopathy. These findings suggest a novel mechanism for and may have significant implications in diabetic cardiac complications.
authors.affiliation: Institutes of Biology and Medical Sciences, Soochow University, Suzhou, Jiangsu Province, China Department of Medicine, Lawson Health Research Institute, University of Western Ontario, London, Ontario, Canada Department of Pathology, Lawson Health Research Institute, University of Western Ontario, London, Ontario, Canada.
authors.forename: Rui
authors.initials: R
authors.lastname: Ni
authors.affiliation: Institutes of Biology and Medical Sciences, Soochow University, Suzhou, Jiangsu Province, China Department of Medicine, Lawson Health Research Institute, University of Western Ontario, London, Ontario, Canada Department of Pathology, Lawson Health Research Institute, University of Western Ontario, London, Ontario, Canada.
authors.forename: Dong
authors.initials: D
authors.lastname: Zheng
authors.affiliation: Institutes of Biology and Medical Sciences, Soochow University, Suzhou, Jiangsu Province, China.
authors.forename: Sidong
authors.initials: S
authors.lastname: Xiong
authors.affiliation: Department of Medicine, Lawson Health Research Institute, University of Western Ontario, London, Ontario, Canada.
authors.forename: David J
authors.initials: DJ
authors.lastname: Hill
authors.affiliation: Department of Medicine, Lawson Health Research Institute, University of Western Ontario, London, Ontario, Canada.
authors.forename: Tao
authors.initials: T
authors.lastname: Sun
authors.affiliation: Department of Biology, Lawson Health Research Institute, University of Western Ontario, London, Ontario, Canada.
authors.forename: Richard B
authors.initials: RB
authors.lastname: Gardiner
authors.affiliation: Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, OH.
authors.forename: Guo-Chang
authors.initials: GC
authors.lastname: Fan
authors.affiliation: Key Laboratory of Transplant Engineering and Immunology, Ministry of Health, Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu, China.
authors.forename: Yanrong
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Division of Endocrinology and Metabolism, Fraternal Order of Eagles Diabetes Research Center, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA.
authors.forename: E Dale
authors.initials: ED
authors.lastname: Abel
authors.affiliation: Division of Cancer Biology and Genetics, Queen's University Cancer Research Institute, and Department of Pathology and Molecular Medicine, Queen's University, Kingston, Ontario, Canada.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Greer
authors.affiliation: Institutes of Biology and Medical Sciences, Soochow University, Suzhou, Jiangsu Province, China Department of Medicine, Lawson Health Research Institute, University of Western Ontario, London, Ontario, Canada Department of Pathology, Lawson Health Research Institute, University of Western Ontario, London, Ontario, Canada tpeng2@uwo.ca.
authors.forename: Tianqing
authors.initials: T
authors.lastname: Peng
mesh_terms: D000818:Animals; D017209:Apoptosis; D002135:Calcium-Binding Proteins / Q000235:genetics; D002154:Calpain / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000150:complications / Q000378:metabolism*; D058065:Diabetic Cardiomyopathies / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D051379:Mice; D008822:Mice, Transgenic; D008929:Mitochondria, Heart / Q000378:metabolism*; D025261:Mitochondrial Proton-Translocating ATPases / Q000235:genetics* / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism*
chemical_list: D002135:Calcium-Binding Proteins; D017382:Reactive Oxygen Species; D013481:Superoxides; C033668:calpastatin; D002154:Calpain; C112682:Capn1 protein, mouse; D025261:Mitochondrial Proton-Translocating ATPases