Institute for Biomedicine, Eurac Research, Affiliated Institute of the University of Lübeck, Bolzano, Italy.
Luxembourg Centre for Systems Biomedicine, University of Luxembourg, L-4362, Esch-sur-Alzette, Luxembourg.
Cell Mol Life Sci. 2022 May 5;79(5):283. doi: 10.1007/s00018-022-04304-3.
Mitochondria play important roles in the regulation of key cellular processes, including energy metabolism, oxidative stress response, and signaling towards cell death or survival, and are distinguished by carrying their own genome (mtDNA). Mitochondrial dysfunction has emerged as a prominent cellular mechanism involved in neurodegeneration, including Parkinson's disease (PD), a neurodegenerative movement disorder, characterized by progressive loss of dopaminergic neurons and the occurrence of proteinaceous Lewy body inclusions. The contribution of mtDNA variants to PD pathogenesis has long been debated and is still not clearly answered. Cytoplasmic hybrid (cybrid) cell models provided evidence for a contribution of mtDNA variants to the PD phenotype. However, conclusive evidence of mtDNA mutations as genetic cause of PD is still lacking. Several models have shown a role of somatic, rather than inherited mtDNA variants in the impairment of mitochondrial function and neurodegeneration. Accordingly, several nuclear genes driving inherited forms of PD are linked to mtDNA quality control mechanisms, and idiopathic as well as familial PD tissues present increased mtDNA damage. In this review, we highlight the use of cybrids in this PD research field and summarize various aspects of how and to what extent mtDNA variants may contribute to the etiology of PD.
线粒体在调节关键细胞过程中发挥着重要作用，包括能量代谢、氧化应激反应以及细胞死亡或存活的信号转导，其特点是携带自己的基因组（mtDNA）。线粒体功能障碍已成为神经退行性变的一个突出的细胞机制，包括帕金森病（PD），一种神经退行性运动障碍，其特征是多巴胺能神经元进行性丧失和出现蛋白性路易小体包涵体。mtDNA 变体对 PD 发病机制的贡献一直存在争议，目前仍未得到明确解答。细胞质杂种（cybrid）细胞模型为 mtDNA 变体对 PD 表型的贡献提供了证据。然而，mtDNA 突变作为 PD 的遗传原因的确切证据仍然缺乏。一些模型表明，体细胞而非遗传的 mtDNA 变体在损害线粒体功能和神经退行性变中起作用。因此，一些导致遗传性 PD 的核基因与 mtDNA 质量控制机制有关，而特发性和家族性 PD 组织存在增加的 mtDNA 损伤。在这篇综述中，我们强调了 cybrid 在这个 PD 研究领域的应用，并总结了 mtDNA 变体可能在多大程度上以及如何导致 PD 病因的各种方面。
