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

Tim König; Simon E Tröder; Kavya Bakka; Anne Korwitz; Ricarda Richter-Dennerlein; Philipp A Lampe; Maria Patron; Mareike Mühlmeister; Sergio Guerrero-Castillo; Ulrich Brandt; Thorsten Decker; Ines Lauria; Angela Paggio; Rosario Rizzuto; Elena I Rugarli; Diego De Stefani; Thomas Langer

doi:10.1016/j.molcel.2016.08.020

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. Epub 2016 Sep 15.

Authors

Tim König¹, Simon E Tröder¹, Kavya Bakka¹, Anne Korwitz¹, Ricarda Richter-Dennerlein¹, Philipp A Lampe¹, Maria Patron¹, Mareike Mühlmeister², Sergio Guerrero-Castillo², Ulrich Brandt², Thorsten Decker¹, Ines Lauria¹, Angela Paggio³, Rosario Rizzuto³, Elena I Rugarli¹, Diego De Stefani³, Thomas Langer⁴

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.

MeSH terms

ATP-Dependent Proteases / genetics
ATP-Dependent Proteases / metabolism
ATPases Associated with Diverse Cellular Activities
Animals
Calcium / metabolism
Calcium Channels / genetics
Calcium Channels / metabolism*
Calcium-Calmodulin-Dependent Protein Kinase Type 2 / genetics
Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism
Cell Death
Cerebellum / metabolism*
Cerebellum / pathology
Corpus Striatum / metabolism*
Corpus Striatum / pathology
Gene Expression Regulation
HEK293 Cells
Hippocampus / metabolism*
Hippocampus / pathology
Homeostasis / genetics
Humans
Ion Transport
Metalloendopeptidases / deficiency
Metalloendopeptidases / genetics*
Mice
Mice, Inbred C57BL
Mice, Transgenic
Mitochondria / metabolism*
Mitochondria / pathology
Mitochondrial Membrane Transport Proteins / genetics
Mitochondrial Membrane Transport Proteins / metabolism
Mitochondrial Permeability Transition Pore
Neurons / metabolism*
Neurons / pathology
Protein Interaction Mapping
Signal Transduction

Substances

Calcium Channels
Mitochondrial Membrane Transport Proteins
Mitochondrial Permeability Transition Pore
mitochondrial calcium uniporter
Calcium-Calmodulin-Dependent Protein Kinase Type 2
ATP-Dependent Proteases
Afg3l2 protein, mouse
Metalloendopeptidases
m-AAA proteases
ATPases Associated with Diverse Cellular Activities
Calcium