title: Deletion of Cyclophilin D Impairs β-Oxidation and Promotes Glucose Metabolism.
abstract: Cyclophilin D (CypD) is a mitochondrial matrix protein implicated in cell death, but a potential role in bioenergetics is not understood. Here, we show that loss or depletion of CypD in cell lines and mice induces defects in mitochondrial bioenergetics due to impaired fatty acid β-oxidation. In turn, CypD loss triggers a global compensatory shift towards glycolysis, with transcriptional upregulation of effectors of glucose metabolism, increased glucose consumption and higher ATP production. In vivo, the glycolytic shift secondary to CypD deletion is associated with expansion of insulin-producing β-cells, mild hyperinsulinemia, improved glucose tolerance, and resistance to high fat diet-induced liver damage and weight gain. Therefore, CypD is a novel regulator of mitochondrial bioenergetics, and unexpectedly controls glucose homeostasis, in vivo.
authors.affiliation: Prostate Cancer Discovery and Development Program, Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104.
authors.forename: Michele
authors.initials: M
authors.lastname: Tavecchio
authors.affiliation: Prostate Cancer Discovery and Development Program, Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104.
authors.forename: Sofia
authors.initials: S
authors.lastname: Lisanti
authors.affiliation: Michael Palmieri Metabolic Laboratory, Children's Hospital of Philadelphia and Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Bennett
authors.affiliation: Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107.
authors.forename: Lucia R
authors.initials: LR
authors.lastname: Languino
authors.affiliation: Prostate Cancer Discovery and Development Program, Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104.
authors.forename: Dario C
authors.initials: DC
authors.lastname: Altieri
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D050260:Carbohydrate Metabolism / Q000502:physiology*; D002478:Cells, Cultured; D002784:Cholesterol / Q000097:blood; D002952:Citric Acid Cycle; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D059305:Diet, High-Fat; D005260:Female; D005951:Glucose Tolerance Test; D006019:Glycolysis; D007150:Immunohistochemistry; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism; D015227:Lipid Peroxidation; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D010179:Pancreas / Q000378:metabolism / Q000473:pathology; D014280:Triglycerides / Q000097:blood
chemical_list: D001786:Blood Glucose; D000081406:Peptidyl-Prolyl Isomerase F; D007328:Insulin; C000631446:PPIF protein, mouse; D014280:Triglycerides; D000255:Adenosine Triphosphate; D002784:Cholesterol; D021983:Cyclophilins