title: MICU1 is an essential gatekeeper for MCU-mediated mitochondrial Ca(2+) uptake that regulates cell survival.
abstract: Mitochondrial Ca(2+) (Ca(2+)(m)) uptake is mediated by an inner membrane Ca(2+) channel called the uniporter. Ca(2+) uptake is driven by the considerable voltage present across the inner membrane (ΔΨ(m)) generated by proton pumping by the respiratory chain. Mitochondrial matrix Ca(2+) concentration is maintained five to six orders of magnitude lower than its equilibrium level, but the molecular mechanisms for how this is achieved are not clear. Here, we demonstrate that the mitochondrial protein MICU1 is required to preserve normal [Ca(2+)](m) under basal conditions. In its absence, mitochondria become constitutively loaded with Ca(2+), triggering excessive reactive oxygen species generation and sensitivity to apoptotic stress. MICU1 interacts with the uniporter pore-forming subunit MCU and sets a Ca(2+) threshold for Ca(2+)(m) uptake without affecting the kinetic properties of MCU-mediated Ca(2+) uptake. Thus, MICU1 is a gatekeeper of MCU-mediated Ca(2+)(m) uptake that is essential to prevent [Ca(2+)](m) overload and associated stress.
authors.affiliation: Department of Biochemistry, Temple University, Philadelphia, PA 19140, USA.
authors.forename: Karthik
authors.initials: K
authors.lastname: Mallilankaraman
authors.forename: Patrick
authors.initials: P
authors.lastname: Doonan
authors.forename: César
authors.initials: C
authors.lastname: Cárdenas
authors.forename: Harish C
authors.initials: HC
authors.lastname: Chandramoorthy
authors.forename: Marioly
authors.initials: M
authors.lastname: Müller
authors.forename: Russell
authors.initials: R
authors.lastname: Miller
authors.forename: Nicholas E
authors.initials: NE
authors.lastname: Hoffman
authors.forename: Rajesh Kumar
authors.initials: RK
authors.lastname: Gandhirajan
authors.forename: Jordi
authors.initials: J
authors.lastname: Molgó
authors.forename: Morris J
authors.initials: MJ
authors.lastname: Birnbaum
authors.forename: Brad S
authors.initials: BS
authors.lastname: Rothberg
authors.forename: Don-On Daniel
authors.initials: DO
authors.lastname: Mak
authors.forename: J Kevin
authors.initials: JK
authors.lastname: Foskett
authors.forename: Muniswamy
authors.initials: M
authors.lastname: Madesh
mesh_terms: D017209:Apoptosis; D002118:Calcium / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D027682:Cation Transport Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002470:Cell Survival; D055785:Gene Knockdown Techniques; D006367:HeLa Cells; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000378:metabolism
chemical_list: D002135:Calcium-Binding Proteins; D027682:Cation Transport Proteins; C116241:MICU1 protein, human; D033681:Mitochondrial Membrane Transport Proteins; D002118:Calcium