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

TitleThe m-AAA Protease Associated with Neurodegeneration Limits MCU Activity in Mitochondria.
Publication TypeJournal Article
Year of Publication2016
AuthorsKönig, T, Tröder, SE, Bakka, K, Korwitz, A, Richter-Dennerlein, R, Lampe, PA, Patron, M, Mühlmeister, M, Guerrero-Castillo, S, Brandt, U, Decker, T, Lauria, I, Paggio, A, Rizzuto, R, Rugarli, EI, De Stefani, D, Langer, T
JournalMol Cell
Date Published2016 Oct 06

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 Ca(2+) 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 Ca(2+) overload, mitochondrial permeability transition pore opening, and neuronal death. Together, our results explain neuronal loss in m-AAA protease deficiency by deregulated mitochondrial Ca(2+) homeostasis.

Alternate JournalMol. Cell
Citation Key10.1016/j.molcel.2016.08.020
PubMed ID27642048