| First Author | König T | Year | 2016 |
| Journal | Mol Cell | Volume | 64 |
| Issue | 1 | Pages | 148-162 |
| PubMed ID | 27642048 | Mgi Jnum | J:248860 |
| Mgi Id | MGI:6094733 | Doi | 10.1016/j.molcel.2016.08.020 |
| Citation | Konig T, et al. (2016) The m-AAA Protease Associated with Neurodegeneration Limits MCU Activity in Mitochondria. Mol Cell 64(1):148-162 |
| abstractText | 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. |
