Developmental Toxicology Laboratory, Systems Toxicology and Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhavan, 31, Mahatma Gandhi Marg, Lucknow, Uttar Pradesh, 226001, India.
Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India.
Mol Neurobiol. 2021 Apr;58(4):1418-1437. doi: 10.1007/s12035-020-02200-0. Epub 2020 Nov 12.
Mitochondria play an essential role in maintaining energy homeostasis and cellular survival. In the brain, higher ATP production is required by mature neurons for communication. Most of the mitochondrial proteins transcribe in the nucleus and import in mitochondria through different pathways of the mitochondrial protein import machinery. This machinery plays a crucial role in determining mitochondrial morphology and functions through mitochondrial biogenesis. Failure of this machinery and any alterations during mitochondrial biogenesis underlies neurodegeneration resulting in Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD) etc. Current knowledge has revealed the different pathways of mitochondrial protein import machinery such as translocase of the outer mitochondrial membrane complex, the presequence pathway, carrier pathway, β-barrel pathway, and mitochondrial import and assembly machinery etc. In this review, we have discussed the recent studies regarding protein import machinery, beyond the well-known effects of increased oxidative stress and bioenergetics dysfunctions. We have elucidated in detail how these types of machinery help to import and locate the precursor proteins to their specific location inside the mitochondria and play a major role in mitochondrial biogenesis. We further discuss their involvement in mitochondrial dysfunctioning and the induction of toxic aggregates in neurodegenerative diseases like AD and PD. The review supports the importance of import machinery in neuronal functions and its association with toxic aggregated proteins in mitochondrial impairment, suggesting a critical role in fostering and maintaining neurodegeneration and therapeutic response.
线粒体在维持能量平衡和细胞存活方面起着至关重要的作用。在大脑中，成熟神经元需要更高的 ATP 产量来进行通讯。大多数线粒体蛋白在核中转录，并通过不同的线粒体蛋白输入机制途径输入线粒体。该机制通过线粒体生物发生在决定线粒体形态和功能方面起着至关重要的作用。该机制的故障以及线粒体生物发生过程中的任何改变都会导致神经退行性疾病，如阿尔茨海默病（AD）、肌萎缩侧索硬化症（ALS）和帕金森病（PD）等。目前的知识已经揭示了线粒体蛋白输入机制的不同途径，如外膜转位酶复合物、前导序列途径、载体途径、β-桶途径和线粒体输入和组装机制等。在这篇综述中，我们讨论了蛋白质输入机制的最新研究，超越了众所周知的氧化应激增加和生物能功能障碍的影响。我们详细阐明了这些类型的机制如何帮助将前体蛋白输入到线粒体的特定位置，并在线粒体生物发生中发挥主要作用。我们进一步讨论了它们在神经退行性疾病（如 AD 和 PD）中线粒体功能障碍和诱导毒性聚集中的作用。该综述支持了输入机制在神经元功能中的重要性及其与线粒体损伤中毒性聚集蛋白的关联，表明其在促进和维持神经退行性变和治疗反应方面具有关键作用。
