title: Tom70 serves as a molecular switch to determine pathological cardiac hypertrophy.
abstract: Pathological cardiac hypertrophy is an inevitable forerunner of heart failure. Regardless of the etiology of cardiac hypertrophy, cardiomyocyte mitochondrial alterations are always observed in this context. The translocases of mitochondrial outer membrane (Tom) complex governs the import of mitochondrial precursor proteins to maintain mitochondrial function under pathophysiological conditions; however, its role in the development of pathological cardiac hypertrophy remains unclear. Here, we showed that Tom70 was downregulated in pathological hypertrophic hearts from humans and experimental animals. The reduction in Tom70 expression produced distinct pathological cardiomyocyte hypertrophy both in vivo and in vitro. The defective mitochondrial import of Tom70-targeted optic atrophy-1 triggered intracellular oxidative stress, which led to a pathological cellular response. Importantly, increased Tom70 levels provided cardiomyocytes with full resistance to diverse pro-hypertrophic insults. Together, these results reveal that Tom70 acts as a molecular switch that orchestrates hypertrophic stresses and mitochondrial responses to determine pathological cardiac hypertrophy.
authors.affiliation: 1] Key Laboratory of Basic Research in Cardiology of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai 200120, China [2] Institute of Medical Genetics, Tongji University, Shanghai 200092, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.affiliation: 1] Key Laboratory of Basic Research in Cardiology of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai 200120, China [2] Department of Cardiology, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.
authors.forename: Man
authors.initials: M
authors.lastname: Qi
authors.affiliation: 1] Key Laboratory of Basic Research in Cardiology of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai 200120, China [2] Department of Cardiology, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.
authors.forename: Changming
authors.initials: C
authors.lastname: Li
authors.affiliation: 1] Key Laboratory of Basic Research in Cardiology of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai 200120, China [2] Institute of Medical Genetics, Tongji University, Shanghai 200092, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Shi
authors.affiliation: 1] Key Laboratory of Basic Research in Cardiology of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai 200120, China [2] Institute of Medical Genetics, Tongji University, Shanghai 200092, China.
authors.forename: Dasheng
authors.initials: D
authors.lastname: Zhang
authors.affiliation: 1] Key Laboratory of Basic Research in Cardiology of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai 200120, China [2] Department of Cardiology, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.
authors.forename: Duanyang
authors.initials: D
authors.lastname: Xie
authors.affiliation: 1] Key Laboratory of Basic Research in Cardiology of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai 200120, China [2] Institute of Medical Genetics, Tongji University, Shanghai 200092, China.
authors.forename: Tianyou
authors.initials: T
authors.lastname: Yuan
authors.affiliation: 1] Key Laboratory of Basic Research in Cardiology of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai 200120, China [2] Department of Cardiology, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Feng
authors.affiliation: 1] Key Laboratory of Basic Research in Cardiology of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai 200120, China [2] Institute of Medical Genetics, Tongji University, Shanghai 200092, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
authors.affiliation: 1] Key Laboratory of Basic Research in Cardiology of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai 200120, China [2] Institute of Medical Genetics, Tongji University, Shanghai 200092, China.
authors.forename: Dandan
authors.initials: D
authors.lastname: Liang
authors.affiliation: 1] Key Laboratory of Basic Research in Cardiology of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai 200120, China [2] Institute of Medical Genetics, Tongji University, Shanghai 200092, China.
authors.forename: Xinran
authors.initials: X
authors.lastname: Xu
authors.affiliation: 1] Key Laboratory of Basic Research in Cardiology of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai 200120, China [2] Department of Cardiology, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.
authors.forename: Jinjin
authors.initials: J
authors.lastname: Chen
authors.affiliation: 1] Key Laboratory of Basic Research in Cardiology of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai 200120, China [2] Institute of Medical Genetics, Tongji University, Shanghai 200092, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Xu
authors.affiliation: 1] Key Laboratory of Basic Research in Cardiology of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai 200120, China [2] Institute of Medical Genetics, Tongji University, Shanghai 200092, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
authors.affiliation: 1] Key Laboratory of Basic Research in Cardiology of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai 200120, China [2] Department of Cardiology, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.
authors.forename: Jiangchuan
authors.initials: J
authors.lastname: Ye
authors.affiliation: 1] Key Laboratory of Basic Research in Cardiology of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai 200120, China [2] Department of Cardiology, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Lv
authors.affiliation: 1] Key Laboratory of Basic Research in Cardiology of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai 200120, China [2] Department of Cardiology, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Huang
authors.affiliation: Department of Pathology and Pathophysiology, Tongji University School of Medicine, Shanghai 200092, China.
authors.forename: Luying
authors.initials: L
authors.lastname: Peng
authors.affiliation: 1] Key Laboratory of Basic Research in Cardiology of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai 200120, China [2] Institute of Medical Genetics, Tongji University, Shanghai 200092, China [3] Department of Cardiology, East Hospital, Tongji University School of Medicine, Shanghai 200120, China [4] Department of Pathology and Pathophysiology, Tongji University School of Medicine, Shanghai 200092, China.
authors.forename: Yi-Han
authors.initials: YH
authors.lastname: Chen
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D015536:Down-Regulation; D006333:Heart Failure / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D033681:Mitochondrial Membrane Transport Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D018384:Oxidative Stress; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015027:Zebrafish / Q000378:metabolism
chemical_list: D033681:Mitochondrial Membrane Transport Proteins; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D034741:RNA, Small Interfering; C402118:TOMM70 protein, human