Koenig, Tim, Troeder, Simon E., Bakka, Kavya, Korwitz, Anne, Richter-Dennerlein, Ricarda, Lampe, Philipp A., Patron, Maria, Muhlmeister, Mareike, Guerrero-Castillo, Sergio ORCID: 0000-0002-6630-0562, Brandt, Ulrich ORCID: 0000-0003-1869-6811, Decker, Thorsten, Lauria, Ines ORCID: 0000-0001-5813-3103, Paggio, Angela, Rizzuto, Rosario ORCID: 0000-0001-7044-5097, Rugarli, Elena I. ORCID: 0000-0002-5782-1067, De Stefani, Diego ORCID: 0000-0003-3796-8907 and Langer, Thomas ORCID: 0000-0003-1250-1462 (2016). The m-AAA Protease Associated with Neurodegeneration Limits MCU Activity in Mitochondria. Mol. Cell, 64 (1). S. 148 - 163. CAMBRIDGE: CELL PRESS. ISSN 1097-4164

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Abstract

Mutations in subunits of mitochondrialm-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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Koenig, TimUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Troeder, Simon E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bakka, KavyaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Korwitz, AnneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Richter-Dennerlein, RicardaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lampe, Philipp A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Patron, MariaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Muhlmeister, MareikeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Guerrero-Castillo, SergioUNSPECIFIEDorcid.org/0000-0002-6630-0562UNSPECIFIED
Brandt, UlrichUNSPECIFIEDorcid.org/0000-0003-1869-6811UNSPECIFIED
Decker, ThorstenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lauria, InesUNSPECIFIEDorcid.org/0000-0001-5813-3103UNSPECIFIED
Paggio, AngelaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rizzuto, RosarioUNSPECIFIEDorcid.org/0000-0001-7044-5097UNSPECIFIED
Rugarli, Elena I.UNSPECIFIEDorcid.org/0000-0002-5782-1067UNSPECIFIED
De Stefani, DiegoUNSPECIFIEDorcid.org/0000-0003-3796-8907UNSPECIFIED
Langer, ThomasUNSPECIFIEDorcid.org/0000-0003-1250-1462UNSPECIFIED
URN: urn:nbn:de:hbz:38-258557
DOI: 10.1016/j.molcel.2016.08.020
Journal or Publication Title: Mol. Cell
Volume: 64
Number: 1
Page Range: S. 148 - 163
Date: 2016
Publisher: CELL PRESS
Place of Publication: CAMBRIDGE
ISSN: 1097-4164
Language: English
Faculty: Faculty of Mathematics and Natural Sciences
Divisions: Faculty of Mathematics and Natural Sciences > Department of Biology > Institute for Genetics
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
HEREDITARY SPASTIC PARAPLEGIA; PERMEABILITY TRANSITION PORE; CALCIUM UNIPORTER; CA2+ UPTAKE; CELL-SURVIVAL; ATP SYNTHASE; COMPLEX; MICU1; AFG3L2; COMPONENTMultiple languages
Biochemistry & Molecular Biology; Cell BiologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/25855

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