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Journal Article

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

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Patron,  M.
Department Langer - Mitochondrial Proteostasis, Max Planck Institute for Biology of Ageing, Max Planck Society;

/persons/resource/persons278030

Langer,  T.
Department Langer - Mitochondrial Proteostasis, Max Planck Institute for Biology of Ageing, Max Planck Society;

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https://www.ncbi.nlm.nih.gov/pubmed/27642048
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Citation

Koenig, T., Troder, S. E., Bakka, K., Korwitz, A., Richter-Dennerlein, R., Lampe, P. A., et al. (2016). The m-AAA Protease Associated with Neurodegeneration Limits MCU Activity in Mitochondria. Mol Cell, 64(1), 148-162. doi:10.1016/j.molcel.2016.08.020.


Cite as: https://hdl.handle.net/21.11116/0000-000B-7150-B
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 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.