Manini Arianna, Abati Elena, Comi Giacomo Pietro, Corti Stefania, Ronchi Dario
Dino Ferrari Center, Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy.
Dino Ferrari Center, Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy; Neuromuscular and Rare Diseases Unit, Department of Neuroscience, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
Ageing Res Rev. 2022 Apr;76:101578. doi: 10.1016/j.arr.2022.101578. Epub 2022 Jan 31.
Maintenance of mitochondrial DNA (mtDNA) homeostasis includes a variety of processes, such as mtDNA replication, repair, and nucleotides synthesis, aimed at preserving the structural and functional integrity of mtDNA molecules. Mutations in several nuclear genes (i.e., POLG, POLG2, TWNK, OPA1, DGUOK, MPV17, TYMP) impair mtDNA maintenance, leading to clinical syndromes characterized by mtDNA depletion and/or deletions in affected tissues. In the past decades, studies have demonstrated a progressive accumulation of multiple mtDNA deletions in dopaminergic neurons of the substantia nigra in elderly population and, to a greater extent, in Parkinson's disease patients. Moreover, parkinsonism has been frequently described as a prominent clinical feature in mtDNA instability syndromes. Among Parkinson's disease-related genes with a significant role in mitochondrial biology, PARK2 and LRRK2 specifically take part in mtDNA maintenance. Moreover, a variety of murine models (i.e., "Mutator", "MitoPark", "PD-mitoPstI", "Deletor", "Twinkle-dup" and "TwinkPark") provided in vivo evidence that mtDNA stability is required to preserve nigrostriatal integrity. Here, we review and discuss the clinical, genetic, and pathological background underlining the link between impaired mtDNA homeostasis and dopaminergic degeneration.
线粒体DNA（mtDNA）稳态的维持包括多种过程，如mtDNA复制、修复和核苷酸合成，旨在保持mtDNA分子的结构和功能完整性。几个核基因（即POLG、POLG2、TWNK、OPA1、DGUOK、MPV17、TYMP）的突变会损害mtDNA的维持，导致以受影响组织中mtDNA耗竭和/或缺失为特征的临床综合征。在过去几十年中，研究表明，老年人群黑质多巴胺能神经元中多种mtDNA缺失逐渐积累，在帕金森病患者中积累程度更高。此外，帕金森综合征常被描述为mtDNA不稳定综合征的一个突出临床特征。在对线粒体生物学具有重要作用的帕金森病相关基因中，PARK2和LRRK2特别参与mtDNA的维持。此外，多种小鼠模型（即“Mutator”、“MitoPark”、“PD-mitoPstI”、“Deletor”、“Twinkle-dup”和“TwinkPark”）提供了体内证据，表明mtDNA稳定性对于维持黑质纹状体完整性是必需的。在此，我们回顾并讨论了强调mtDNA稳态受损与多巴胺能神经元变性之间联系的临床、遗传和病理背景。
