title: The physiological role of mitochondrial calcium revealed by mice lacking the mitochondrial calcium uniporter.
abstract: Mitochondrial calcium has been postulated to regulate a wide range of processes from bioenergetics to cell death. Here, we characterize a mouse model that lacks expression of the recently discovered mitochondrial calcium uniporter (MCU). Mitochondria derived from MCU(-/-) mice have no apparent capacity to rapidly uptake calcium. Whereas basal metabolism seems unaffected, the skeletal muscle of MCU(-/-) mice exhibited alterations in the phosphorylation and activity of pyruvate dehydrogenase. In addition, MCU(-/-) mice exhibited marked impairment in their ability to perform strenuous work. We further show that mitochondria from MCU(-/-) mice lacked evidence for calcium-induced permeability transition pore (PTP) opening. The lack of PTP opening does not seem to protect MCU(-/-) cells and tissues from cell death, although MCU(-/-) hearts fail to respond to the PTP inhibitor cyclosporin A. Taken together, these results clarify how acute alterations in mitochondrial matrix calcium can regulate mammalian physiology.
authors.affiliation: 1] Center for Molecular Medicine, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892, USA [2] National Center of Biomedical Analysis, Beijing 100850, China [3].
authors.forename: Xin
authors.initials: X
authors.lastname: Pan
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
authors.forename: Tiffany
authors.initials: T
authors.lastname: Nguyen
authors.forename: Chengyu
authors.initials: C
authors.lastname: Liu
authors.forename: Junhui
authors.initials: J
authors.lastname: Sun
authors.forename: Yanjie
authors.initials: Y
authors.lastname: Teng
authors.forename: Maria M
authors.initials: MM
authors.lastname: Fergusson
authors.forename: Ilsa I
authors.initials: II
authors.lastname: Rovira
authors.forename: Michele
authors.initials: M
authors.lastname: Allen
authors.forename: Danielle A
authors.initials: DA
authors.lastname: Springer
authors.forename: Angel M
authors.initials: AM
authors.lastname: Aponte
authors.forename: Marjan
authors.initials: M
authors.lastname: Gucek
authors.forename: Robert S
authors.initials: RS
authors.lastname: Balaban
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Murphy
authors.forename: Toren
authors.initials: T
authors.lastname: Finkel
mesh_terms: D000818:Animals; D017209:Apoptosis; D002118:Calcium / Q000502:physiology*; D015220:Calcium Channels / Q000172:deficiency / Q000235:genetics*; D002316:Cardiotonic Agents / Q000494:pharmacology; D002478:Cells, Cultured; D017079:Exercise Tolerance / Q000235:genetics; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D056726:Genetic Association Studies; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008931:Mitochondria, Muscle / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D018482:Muscle, Skeletal / Q000378:metabolism / Q000502:physiology; D015428:Myocardial Reperfusion Injury / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D010641:Phenotype; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism
chemical_list: D015220:Calcium Channels; D002316:Cardiotonic Agents; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D011768:Pyruvate Dehydrogenase Complex; C034703:mitochondrial calcium uniporter; D007545:Isoproterenol; D002118:Calcium