Brunetti Dario, Catania Alessia, Viscomi Carlo, Deleidi Michela, Bindoff Laurence A, Ghezzi Daniele, Zeviani Massimo
Department of Medical Biotechnology and Translational Medicine, University of Milan, 20129 Milan, Italy.
Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20126 Milan, Italy.
Biomedicines. 2021 Jul 17;9(7):833. doi: 10.3390/biomedicines9070833.
Mounting evidence shows a link between mitochondrial dysfunction and neurodegenerative disorders, including Alzheimer Disease. Increased oxidative stress, defective mitodynamics, and impaired oxidative phosphorylation leading to decreased ATP production, can determine synaptic dysfunction, apoptosis, and neurodegeneration. Furthermore, mitochondrial proteostasis and the protease-mediated quality control system, carrying out degradation of potentially toxic peptides and misfolded or damaged proteins inside mitochondria, are emerging as potential pathogenetic mechanisms. The enzyme pitrilysin metallopeptidase 1 (PITRM1) is a key player in these processes; it is responsible for degrading mitochondrial targeting sequences that are cleaved off from the imported precursor proteins and for digesting a mitochondrial fraction of amyloid beta (Aβ). In this review, we present current evidence obtained from patients with mutations, as well as the different cellular and animal models of deficiency, which points toward PITRM1 as a possible driving factor of several neurodegenerative conditions. Finally, we point out the prospect of new diagnostic and therapeutic approaches.
越来越多的证据表明线粒体功能障碍与神经退行性疾病之间存在联系，包括阿尔茨海默病。氧化应激增加、线粒体动力学缺陷以及氧化磷酸化受损导致ATP生成减少，可引发突触功能障碍、细胞凋亡和神经退行性变。此外，线粒体蛋白质稳态以及蛋白酶介导的质量控制系统，负责降解线粒体内部潜在有毒的肽以及错误折叠或受损的蛋白质，正逐渐成为潜在的致病机制。金属蛋白酶1（PITRM1）是这些过程中的关键参与者；它负责降解从导入的前体蛋白上切割下来的线粒体靶向序列，并消化淀粉样β蛋白（Aβ）的线粒体部分。在这篇综述中，我们展示了从携带突变的患者以及PITRM1缺乏的不同细胞和动物模型中获得的现有证据，这些证据表明PITRM1可能是几种神经退行性疾病的驱动因素。最后，我们指出了新的诊断和治疗方法的前景。
