title: Cyclophilin D regulates mitochondrial flashes and metabolism in cardiac myocytes.
abstract: Cyclophilin D (CyP-D) is the mitochondrial-specific member of the evolutionally conserved cyclophilin family, and plays an important role in the regulation of mitochondrial permeability transition (MPT) under stress. Recently we have demonstrated that respiratory mitochondria undergo mitochondrial flash ("mitoflash") activity which is coupled with transient MPT under physiological conditions. However, whether and how CyP-D regulates mitoflashes remain incompletely understood. By using both loss- and gain-of-function approaches in isolated cardiomyocytes, beating hearts, and skeletal muscles in living mice, we revisited the role of CyP-D in the regulation of mitoflashes. Overexpression of CyP-D increased, and knockout of it halved, cardiac mitoflash frequency, while mitoflash amplitude and kinetics remained unaffected. However, CyP-D ablation did not alter mitoflash frequency, with mitoflash amplitude increased, in gastrocnemius muscles. This disparity was accompanied by 4-fold higher CyP-D expression in mouse cardiac than skeletal muscles. The mitochondrial maximal respiration rate and reserved capacity were reduced in CyP-D-null cardiomyocytes. These data indicate that CyP-D is a significant regulator of mitoflash ignition and mitochondrial metabolism in heart. In addition, tissue-specific CyP-D expression may partly explain the differential regulation of mitoflashes in the two types of striated muscles.
authors.affiliation: State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Shang
authors.affiliation: Department of Physiology and Pathophysiology, Health Science Center, Peking University, Beijing 100191, China.
authors.forename: Han
authors.initials: H
authors.lastname: Gao
authors.affiliation: State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China.
authors.forename: Fujian
authors.initials: F
authors.lastname: Lu
authors.affiliation: State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Ma
authors.affiliation: State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China.
authors.forename: Huaqiang
authors.initials: H
authors.lastname: Fang
authors.affiliation: State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Sun
authors.affiliation: State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China.
authors.forename: Jiejia
authors.initials: J
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Ding
authors.affiliation: State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Lin
authors.affiliation: State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China.
authors.forename: Yanru
authors.initials: Y
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China.
authors.forename: Xianhua
authors.initials: X
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China.
authors.forename: Heping
authors.initials: H
authors.lastname: Cheng
authors.affiliation: Department of Physiology and Pathophysiology, Health Science Center, Peking University, Beijing 100191, China. Electronic address: zhengm@bjmu.edu.cn.
authors.forename: Ming
authors.initials: M
authors.lastname: Zheng
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism* / Q000648:ultrastructure; D033681:Mitochondrial Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D018482:Muscle, Skeletal / Q000378:metabolism / Q000648:ultrastructure; D054792:Muscle, Striated / Q000378:metabolism / Q000648:ultrastructure; D009206:Myocardium / Q000378:metabolism* / Q000648:ultrastructure; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000648:ultrastructure; D009924:Organ Culture Techniques; D009928:Organ Specificity; D061251:Primary Cell Culture; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D001426:Bacterial Proteins; D000081406:Peptidyl-Prolyl Isomerase F; D008164:Luminescent Proteins; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; C000631446:PPIF protein, mouse; D017382:Reactive Oxygen Species; C054562:yellow fluorescent protein, Bacteria; D021983:Cyclophilins
keywords: Cyclophilin D; Heart; Metabolism; Mitochondrial flash; Skeletal muscle