关键词： calcium cyclophilin D mitochondrial calcium uniporter mitochondrial permeability transition (MPT) protein processing protein turnover spastic paraplegia 7

Mesh ： ATPases Associated with Diverse Cellular Activities / metabolism physiology Calcium / metabolism Calcium Channels / metabolism Cell Membrane Permeability / physiology HEK293 Cells Humans Metalloendopeptidases / metabolism physiology Mitochondria / metabolism Mitochondrial Membrane Transport Proteins / metabolism physiology Mitochondrial Membranes / metabolism Mitochondrial Permeability Transition Pore Mitochondrial Transmembrane Permeability-Driven Necrosis / physiology Paraplegia / metabolism Proton-Translocating ATPases / metabolism Spastic Paraplegia, Hereditary / metabolism

来  源：   DOI：10.1074/jbc.RA118.006443   PDF(Sci-hub)   PDF(Pubmed)

Abstract：
The mitochondrial matrix ATPase associated with diverse cellular activities (m-AAA) protease spastic paraplegia 7 (SPG7) has been recently implicated as either a negative or positive regulatory component of the mitochondrial permeability transition pore (mPTP) by two research groups. To address this controversy, we investigated possible mechanisms that explain the discrepancies between these two studies. We found that loss of the SPG7 gene increased resistance to Ca2+-induced mPTP opening. However, this occurs independently of cyclophilin D (cyclosporine A insensitive) rather it is through decreased mitochondrial Ca2+ concentrations and subsequent adaptations mediated by impaired formation of functional mitochondrial Ca2+ uniporter complexes. We found that SPG7 directs the m-AAA complex to favor association with the mitochondrial Ca2+ uniporter (MCU) and MCU processing regulates higher order MCU-complex formation. The results suggest that SPG7 does not constitute a core component of the mPTP but can modulate mPTP through regulation of the basal mitochondrial Ca2+ concentration.
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