The m-AAA Protease Associated with Neurodegeneration Limits MCU Activity in Mitochondria

2016 | journal article. A publication with affiliation to the University of Göttingen.

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​The m-AAA Protease Associated with Neurodegeneration Limits MCU Activity in Mitochondria​
Koenig, T.; Troeder, S. E.; Bakka, K.; Korwitz, A.; Richter-Dennerlein, R. ; Lampe, P. A. & Patron, M. et al.​ (2016) 
Molecular Cell64(1) pp. 148​-162​.​ DOI: 

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Koenig, Tim; Troeder, Simon E.; Bakka, Kavya; Korwitz, Anne; Richter-Dennerlein, Ricarda ; Lampe, Philipp A.; Patron, Maria; Muhlmeister, Mareike; Guerrero-Castillo, Sergio; Brandt, Ulrich; Decker, Thorsten; Lauria, Ines; Paggio, Angela; Rizzuto, Rosario; Rugarli, Elena I.; De Stefani, Diego; Langer, Thomas
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.
Issue Date
Cell Press
Molecular Cell 
1097-4164; 1097-2765



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