2. Academic Validation
  3. The m-AAA Protease Associated with Neurodegeneration Limits MCU Activity in Mitochondria

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

  • Mol Cell. 2016 Oct 6;64(1):148-162. doi: 10.1016/j.molcel.2016.08.020.
Tim König 1,  Simon E Tröder 1,  Kavya Bakka 1,  Anne Korwitz 1,  Ricarda Richter-Dennerlein 1,  Philipp A Lampe 1,  Maria Patron 1,  Mareike Mühlmeister 2,  Sergio Guerrero-Castillo 2,  Ulrich Brandt 2,  Thorsten Decker 1,  Ines Lauria 1,  Angela Paggio 3,  Rosario Rizzuto 3,  Elena I Rugarli 1,  Diego De Stefani 3,  Thomas Langer 4
Affiliations

Affiliations

  • 1 Institute for Genetics, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Center for Molecular Medicine (CMMC), University of Cologne, 50931 Cologne, Germany.
  • 2 Nijmegen Center for Mitochondrial Disorders, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands.
  • 3 Department of Biomedical Sciences, University of Padova, 35121 Padova, Italy; CNR Neuroscience Institute, 35121 Padova, Italy.
  • 4 Institute for Genetics, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Center for Molecular Medicine (CMMC), University of Cologne, 50931 Cologne, Germany; Max Planck Institute for Biology of Aging, 50931 Cologne, Germany. Electronic address: thomas.langer@uni-koeln.de.
PMID: 27642048 DOI: 10.1016/j.molcel.2016.08.020
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 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.

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