title: Proteolytic control of the mitochondrial calcium uniporter complex.
abstract: The mitochondrial calcium uniporter is a Ca2+-activated Ca2+channel complex mediating mitochondrial Ca2+uptake, a process crucial for Ca2+signaling, bioenergetics, and cell death. The uniporter is composed of the pore-forming MCU protein, the gatekeeping MICU1 and MICU2 subunits, and EMRE, a single-pass membrane protein that links MCU and MICU1 together. As a bridging subunit required for channel function, EMRE could paradoxically inhibit uniporter complex formation if expressed in excess. Here, we show that mitochondrial mAAA proteases AFG3L2 and SPG7 rapidly degrade unassembled EMRE using the energy of ATP hydrolysis. Once EMRE is incorporated into the complex, its turnover is inhibited >15-fold. Protease-resistant EMRE mutants produce uniporter subcomplexes that induce constitutive Ca2+leakage into mitochondria, a condition linked to debilitating neuromuscular disorders in humans. The results highlight the dynamic nature of uniporter subunit assembly, which must be tightly regulated to ensure proper mitochondrial responses to intracellular Ca2+signals.
authors.affiliation: Department of Biochemistry, Brandeis University, Waltham, MA 02454.|Howard Hughes Medical Institute, Brandeis University, Waltham, MA 02454.
authors.forename: Chen-Wei
authors.initials: CW
authors.lastname: Tsai
authors.affiliation: Department of Biochemistry, Brandeis University, Waltham, MA 02454.|Howard Hughes Medical Institute, Brandeis University, Waltham, MA 02454.
authors.forename: Yujiao
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139.
authors.forename: Ping-Chieh
authors.initials: PC
authors.lastname: Pao
authors.affiliation: Department of Biochemistry, Brandeis University, Waltham, MA 02454.|Howard Hughes Medical Institute, Brandeis University, Waltham, MA 02454.
authors.forename: Charles B
authors.initials: CB
authors.lastname: Phillips
authors.affiliation: Department of Biochemistry, Brandeis University, Waltham, MA 02454.|Howard Hughes Medical Institute, Brandeis University, Waltham, MA 02454.
authors.forename: Carole
authors.initials: C
authors.lastname: Williams
authors.affiliation: Department of Biochemistry, Brandeis University, Waltham, MA 02454; cmiller@brandeis.edu mftsai@brandeis.edu.|Howard Hughes Medical Institute, Brandeis University, Waltham, MA 02454.
authors.forename: Christopher
authors.identifier: 0000-0002-0273-8653
authors.initials: C
authors.lastname: Miller
authors.affiliation: Department of Biochemistry, Brandeis University, Waltham, MA 02454.
authors.forename: Matthew
authors.initials: M
authors.lastname: Ranaghan
authors.affiliation: Department of Biochemistry, Brandeis University, Waltham, MA 02454; cmiller@brandeis.edu mftsai@brandeis.edu.|Howard Hughes Medical Institute, Brandeis University, Waltham, MA 02454.
authors.forename: Ming-Feng
authors.initials: MF
authors.lastname: Tsai
mesh_terms: D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology*; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000502:physiology*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D010447:Peptide Hydrolases / Q000378:metabolism; D021122:Protein Subunits
chemical_list: D015220:Calcium Channels; D021122:Protein Subunits; C585180:SMDT1 protein, human; C034703:mitochondrial calcium uniporter; D010447:Peptide Hydrolases; D002118:Calcium
keywords: EMRE; MCU; mAAA protease