title: The m-AAA Protease Associated with Neurodegeneration Limits MCU Activity in Mitochondria.
abstract: Mutations in subunits of mitochondrial m-AAA proteases in the inner membrane cause neurodegeneration in spinocerebellar ataxia (SCA28) and hereditary spastic paraplegia (HSP7). m-AAA proteases preserve mitochondrial proteostasis, mitochondrial morphology, and efficient OXPHOS activity, but the cause for neuronal loss in disease is unknown. We have determined the neuronal interactome of m-AAA proteases in mice and identified a complex with C2ORF47 (termed MAIP1), which counteracts cell death by regulating the assembly of the mitochondrial Ca2+uniporter MCU. While MAIP1 assists biogenesis of the MCU subunit EMRE, the m-AAA protease degrades non-assembled EMRE and ensures efficient assembly of gatekeeper subunits with MCU. Loss of the m-AAA protease results in accumulation of constitutively active MCU-EMRE channels lacking gatekeeper subunits in neuronal mitochondria and facilitates mitochondrial Ca2+overload, mitochondrial permeability transition pore opening, and neuronal death. Together, our results explain neuronal loss in m-AAA protease deficiency by deregulated mitochondrial Ca2+homeostasis.
authors.affiliation: Institute for Genetics, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Center for Molecular Medicine (CMMC), University of Cologne, 50931 Cologne, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: König
authors.affiliation: Institute for Genetics, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Center for Molecular Medicine (CMMC), University of Cologne, 50931 Cologne, Germany.
authors.forename: Simon E
authors.initials: SE
authors.lastname: Tröder
authors.affiliation: Institute for Genetics, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Center for Molecular Medicine (CMMC), University of Cologne, 50931 Cologne, Germany.
authors.forename: Kavya
authors.initials: K
authors.lastname: Bakka
authors.affiliation: Institute for Genetics, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Center for Molecular Medicine (CMMC), University of Cologne, 50931 Cologne, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Korwitz
authors.affiliation: Institute for Genetics, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Center for Molecular Medicine (CMMC), University of Cologne, 50931 Cologne, Germany.
authors.forename: Ricarda
authors.initials: R
authors.lastname: Richter-Dennerlein
authors.affiliation: Institute for Genetics, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Center for Molecular Medicine (CMMC), University of Cologne, 50931 Cologne, Germany.
authors.forename: Philipp A
authors.initials: PA
authors.lastname: Lampe
authors.affiliation: Institute for Genetics, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Center for Molecular Medicine (CMMC), University of Cologne, 50931 Cologne, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Patron
authors.affiliation: Nijmegen Center for Mitochondrial Disorders, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands.
authors.forename: Mareike
authors.initials: M
authors.lastname: Mühlmeister
authors.affiliation: Nijmegen Center for Mitochondrial Disorders, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands.
authors.forename: Sergio
authors.initials: S
authors.lastname: Guerrero-Castillo
authors.affiliation: Nijmegen Center for Mitochondrial Disorders, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Brandt
authors.affiliation: Institute for Genetics, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Center for Molecular Medicine (CMMC), University of Cologne, 50931 Cologne, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Decker
authors.affiliation: Institute for Genetics, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Center for Molecular Medicine (CMMC), University of Cologne, 50931 Cologne, Germany.
authors.forename: Ines
authors.initials: I
authors.lastname: Lauria
authors.affiliation: Department of Biomedical Sciences, University of Padova, 35121 Padova, Italy; CNR Neuroscience Institute, 35121 Padova, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Paggio
authors.affiliation: Department of Biomedical Sciences, University of Padova, 35121 Padova, Italy; CNR Neuroscience Institute, 35121 Padova, Italy.
authors.forename: Rosario
authors.initials: R
authors.lastname: Rizzuto
authors.affiliation: Institute for Genetics, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Center for Molecular Medicine (CMMC), University of Cologne, 50931 Cologne, Germany.
authors.forename: Elena I
authors.initials: EI
authors.lastname: Rugarli
authors.affiliation: Department of Biomedical Sciences, University of Padova, 35121 Padova, Italy; CNR Neuroscience Institute, 35121 Padova, Italy.
authors.forename: Diego
authors.initials: D
authors.lastname: De Stefani
authors.affiliation: Institute for Genetics, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Center for Molecular Medicine (CMMC), University of Cologne, 50931 Cologne, Germany; Max Planck Institute for Biology of Aging, 50931 Cologne, Germany. Electronic address: thomas.langer@uni-koeln.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Langer
mesh_terms: D049069:ATP-Dependent Proteases / Q000235:genetics / Q000378:metabolism; D000074183:ATPases Associated with Diverse Cellular Activities; D000818:Animals; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics / Q000378:metabolism; D016923:Cell Death; D002531:Cerebellum / Q000378:metabolism* / Q000473:pathology; D003342:Corpus Striatum / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology; D006706:Homeostasis / Q000235:genetics; D006801:Humans; D017136:Ion Transport; D008666:Metalloendopeptidases / Q000172:deficiency / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D033681:Mitochondrial Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D025941:Protein Interaction Mapping; D015398:Signal Transduction
chemical_list: D015220:Calcium Channels; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; C034703:mitochondrial calcium uniporter; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D049069:ATP-Dependent Proteases; C542395:Afg3l2 protein, mouse; D008666:Metalloendopeptidases; C114583:m-AAA proteases; D000074183:ATPases Associated with Diverse Cellular Activities; D002118:Calcium