The m-AAA Protease Associated with Neurodegeneration Limits MCU Activity in Mitochondria
| Autor: | Thomas Langer, Thorsten Decker, Ines Lauria, Ricarda Richter-Dennerlein, Kavya Bakka, Angela Paggio, Maria Patron, Anne Korwitz, Mareike Mühlmeister, Ulrich Brandt, Elena I. Rugarli, Tim König, Simon E. Tröder, Rosario Rizzuto, Philipp A Lampe, Sergio Guerrero-Castillo, Diego De Stefani |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Proteases Protease Protein subunit medicine.medical_treatment Neurodegeneration Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6] Cell Biology Mitochondrion Biology medicine.disease 03 medical and health sciences 030104 developmental biology Proteostasis Biochemistry Mitochondrial permeability transition pore medicine Uniporter Molecular Biology |
| Zdroj: | Mol Cell Molecular Cell, 64, 1, pp. 148-162 Molecular Cell, 64, 148-162 |
| ISSN: | 1097-2765 |
| Popis: | Item does not contain fulltext 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. |
| Databáze: | OpenAIRE |
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