title: MICU1 Serves as a Molecular Gatekeeper to Prevent In Vivo Mitochondrial Calcium Overload.
abstract: MICU1 is a component of the mitochondrial calcium uniporter, a multiprotein complex that also includes MICU2, MCU, and EMRE. Here, we describe a mouse model of MICU1 deficiency. MICU1(-/-) mitochondria demonstrate altered calcium uptake, and deletion of MICU1 results in significant, but not complete, perinatal mortality. Similar to afflicted patients, viable MICU1(-/-) mice manifest marked ataxia and muscle weakness. Early in life, these animals display a range of biochemical abnormalities, including increased resting mitochondrial calcium levels, altered mitochondrial morphology, and reduced ATP. Older MICU1(-/-) mice show marked, spontaneous improvement coincident with improved mitochondrial calcium handling and an age-dependent reduction in EMRE expression. Remarkably, deleting one allele of EMRE helps normalize calcium uptake while simultaneously rescuing the high perinatal mortality observed in young MICU1(-/-) mice. Together, these results demonstrate that MICU1 serves as a molecular gatekeeper preventing calcium overload and suggests that modulating the calcium uniporter could have widespread therapeutic benefits.
authors.affiliation: Center for Molecular Medicine, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Julia C
authors.initials: JC
authors.lastname: Liu
authors.affiliation: Center for Molecular Medicine, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
authors.affiliation: Center for Molecular Medicine, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Kira M
authors.initials: KM
authors.lastname: Holmström
authors.affiliation: Systems Biology Center, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Sara
authors.initials: S
authors.lastname: Menazza
authors.affiliation: Systems Biology Center, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Randi J
authors.initials: RJ
authors.lastname: Parks
authors.affiliation: Center for Molecular Medicine, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Maria M
authors.initials: MM
authors.lastname: Fergusson
authors.affiliation: Pathology Core, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Zu-Xi
authors.initials: ZX
authors.lastname: Yu
authors.affiliation: Murine Phenotyping Core, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Danielle A
authors.initials: DA
authors.lastname: Springer
authors.affiliation: Laboratory of Cancer Biology and Genetics, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Halsey
authors.affiliation: Transgenic Core, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Chengyu
authors.initials: C
authors.lastname: Liu
authors.affiliation: Systems Biology Center, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Murphy
authors.affiliation: Center for Molecular Medicine, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD 20892, USA. Electronic address: finkelt@nih.gov.
authors.forename: Toren
authors.initials: T
authors.lastname: Finkel
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D027682:Cation Transport Proteins / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000502:physiology; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D015220:Calcium Channels; D002135:Calcium-Binding Proteins; D027682:Cation Transport Proteins; C000610715:MICU1 protein, mouse; D033681:Mitochondrial Membrane Transport Proteins; C034703:mitochondrial calcium uniporter; D002118:Calcium