Max Planck Institute for Biology of Aging, Cologne, Germany.
Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Disease (CECAD), and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
Cell Res. 2018 Mar;28(3):296-306. doi: 10.1038/cr.2018.17. Epub 2018 Feb 16.
The function of mitochondria depends on ubiquitously expressed and evolutionary conserved m-AAA proteases in the inner membrane. These ATP-dependent peptidases form hexameric complexes built up of homologous subunits. AFG3L2 subunits assemble either into homo-oligomeric isoenzymes or with SPG7 (paraplegin) subunits into hetero-oligomeric proteolytic complexes. Mutations in AFG3L2 are associated with dominant spinocerebellar ataxia (SCA28) characterized by the loss of Purkinje cells, whereas mutations in SPG7 cause a recessive form of hereditary spastic paraplegia (HSP7) with motor neurons of the cortico-spinal tract being predominantly affected. Pleiotropic functions have been assigned to m-AAA proteases, which act as quality control and regulatory enzymes in mitochondria. Loss of m-AAA proteases affects mitochondrial protein synthesis and respiration and leads to mitochondrial fragmentation and deficiencies in the axonal transport of mitochondria. Moreover m-AAA proteases regulate the assembly of the mitochondrial calcium uniporter (MCU) complex. Impaired degradation of the MCU subunit EMRE in AFG3L2-deficient mitochondria results in the formation of deregulated MCU complexes, increased mitochondrial calcium uptake and increased vulnerability of neurons for calcium-induced cell death. A reduction of calcium influx into the cytosol of Purkinje cells rescues ataxia in an AFG3L2-deficient mouse model. In this review, we discuss the relationship between the m-AAA protease and mitochondrial calcium homeostasis and its relevance for neurodegeneration and describe a novel mouse model lacking MCU specifically in Purkinje cells. Our results pledge for a novel view on m-AAA proteases that integrates their pleiotropic functions in mitochondria to explain the pathogenesis of associated neurodegenerative disorders.
线粒体的功能依赖于普遍表达和进化保守的内膜 m-AAA 蛋白酶。这些依赖 ATP 的肽酶形成由同源亚基组成的六聚体复合物。AFG3L2 亚基要么组装成同型寡聚同工酶，要么与 SPG7（脊髓小脑共济失调 7 号蛋白）亚基组装成异型寡聚蛋白酶复合物。AFG3L2 突变与显性脊髓小脑共济失调（SCA28）相关，其特征是浦肯野细胞丧失，而 SPG7 突变导致隐性遗传性痉挛性截瘫（HSP7），皮质脊髓束运动神经元受到主要影响。m-AAA 蛋白酶具有多种功能，它们作为线粒体的质量控制和调节酶。m-AAA 蛋白酶的缺失会影响线粒体的蛋白质合成和呼吸，并导致线粒体碎片化和线粒体在轴突中的运输缺陷。此外，m-AAA 蛋白酶还调节线粒体钙单向转运体（MCU）复合物的组装。在 AFG3L2 缺陷的线粒体中，MCU 亚基 EMRE 的降解受损，导致 MCU 复合物的形成失控，线粒体摄取钙离子增加，神经元对钙离子诱导的细胞死亡的易感性增加。减少 Purkinje 细胞内钙离子流入胞质可挽救 AFG3L2 缺陷小鼠模型中的共济失调。在这篇综述中，我们讨论了 m-AAA 蛋白酶与线粒体钙动态平衡的关系及其与神经退行性变的相关性，并描述了一种缺乏 MCU 的新型小鼠模型，该模型特异性缺乏 Purkinje 细胞中的 MCU。我们的结果为 m-AAA 蛋白酶的新观点提供了支持，该观点将其在线粒体中的多种功能整合起来，以解释相关神经退行性疾病的发病机制。
