title: The Mitochondrial Permeability Transition Pore Regulator Cyclophilin D Exhibits Tissue-Specific Control of Metabolic Homeostasis.
abstract: The mitochondrial permeability transition pore (mPTP) is a key regulator of mitochondrial function that has been implicated in the pathogenesis of metabolic disease. Cyclophilin D (CypD) is a critical regulator that directly binds to mPTP constituents to facilitate the pore opening. We previously found that global CypD knockout mice (KO) are protected from diet-induced glucose intolerance; however, the tissue-specific function of CypD and mPTP, particularly in the control of glucose homeostasis, has not been ascertained. To this end, we performed calcium retention capacity (CRC) assay to compare the importance of CypD in the liver versus skeletal muscle. We found that liver mitochondria are more dependent on CypD for mPTP opening than skeletal muscle mitochondria. To ascertain the tissue-specific role of CypD in metabolic homeostasis, we generated liver-specific and muscle-specific CypD knockout mice (LKO and MKO, respectively) and fed them either a chow diet or 45% high-fat diet (HFD) for 14 weeks. MKO mice displayed similar body weight gain and glucose intolerance compared with wild type littermates (WT), whereas LKO mice developed greater visceral obesity, glucose intolerance and pyruvate intolerance compared with WT mice. These findings demonstrate that loss of muscle CypD is not sufficient to alter whole body glucose metabolism, while the loss of liver CypD exacerbates obesity and whole-body metabolic dysfunction in mice fed HFD.
authors.affiliation: Department of Medicine, University of Virginia School of Medicine, Charlottesville, VA, United States of America.|Center for Skeletal Muscle Research at Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA, United States of America.
authors.forename: Rhianna C
authors.initials: RC
authors.lastname: Laker
authors.affiliation: Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA, United States of America.
authors.forename: Evan P
authors.initials: EP
authors.lastname: Taddeo
authors.affiliation: Department of Medicine, University of Virginia School of Medicine, Charlottesville, VA, United States of America.|Center for Skeletal Muscle Research at Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA, United States of America.
authors.forename: Yasir N
authors.initials: YN
authors.lastname: Akhtar
authors.affiliation: Department of Medicine, University of Virginia School of Medicine, Charlottesville, VA, United States of America.|Center for Skeletal Muscle Research at Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA, United States of America.
authors.forename: Mei
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Center for Skeletal Muscle Research at Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA, United States of America.|Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA, United States of America.
authors.forename: Kyle L
authors.initials: KL
authors.lastname: Hoehn
authors.affiliation: Department of Medicine, University of Virginia School of Medicine, Charlottesville, VA, United States of America.|Center for Skeletal Muscle Research at Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA, United States of America.|Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA, United States of America.|Department of Molecular Physiology & Biological Physics, University of Virginia School of Medicine, Charlottesville, VA, United States of America.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Yan
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000502:physiology*; D006706:Homeostasis / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008929:Mitochondria, Heart / Q000378:metabolism*; D008930:Mitochondria, Liver / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism*; D000083162:Mitochondrial Permeability Transition Pore
chemical_list: D000081406:Peptidyl-Prolyl Isomerase F; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; C000631446:PPIF protein, mouse; D021983:Cyclophilins; D002118:Calcium