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