Department of Biology, College of Arts and Sciences, Rutgers University, NJ, USA.
Center for Computational and Integrative Biology, Rutgers University, NJ, USA.
Pharmacol Res. 2021 Jan;163:105211. doi: 10.1016/j.phrs.2020.105211. Epub 2020 Oct 1.
Mitochondrial dysfunction - including increased apoptosis, calcium and protein dyshomeostasis within the organelle, and dysfunctional bioenergetics and oxidative status - is a common, early feature in all the major neurodegenerative diseases, including Alzheimer's Disease (AD) and Parkinson's Disease (PD). However, the exact molecular mechanisms that drive the organelle to dysfunction and ultimately to failure in these conditions are still not well described. Different authors have shown that inorganic polyphosphate (polyP), an ancient and well-conserved molecule, plays a key role in the regulation of mitochondrial physiology under basal conditions. PolyP, which is present in all studied organisms, is composed of chains of orthophosphates linked together by highly energetic phosphoanhydride bonds, similar to those found in ATP. This polymer shows a ubiquitous distribution, even if a high co-localization with mitochondria has been reported. It has been proposed that polyP might be an alternative to ATP for cellular energy storage in different organisms, as well as the implication of polyP in the regulation of many of the mitochondrial processes affected in AD and PD, including protein and calcium homeostasis. Here, we conduct a comprehensive review and discussion of the bibliography available regarding the role of polyP in the mitochondrial dysfunction present in AD and PD. Taking into account the data presented in this review, we postulate that polyP could be a valid, innovative and, plausible pharmacological target against mitochondrial dysfunction in AD and PD. However, further research should be conducted to better understand the exact role of polyP in neurodegeneration, as well as the metabolism of the polymer, and the effect of different lengths of polyP on cellular and mitochondrial physiology.
线粒体功能障碍——包括凋亡增加、细胞器内钙和蛋白质稳态失调以及生物能量和氧化状态功能障碍——是所有主要神经退行性疾病（包括阿尔茨海默病 (AD) 和帕金森病 (PD)）的共同的早期特征。然而，导致细胞器在这些情况下功能障碍并最终衰竭的确切分子机制仍未得到很好的描述。不同的作者已经表明，无机多聚磷酸盐（polyP），一种古老而高度保守的分子，在基础条件下调节线粒体生理学中起着关键作用。多聚磷酸盐存在于所有研究过的生物体中，由通过高能磷酸酐键连接在一起的 orthophosphates 链组成，类似于 ATP 中发现的键。这种聚合物具有普遍的分布，即使已经报道了与线粒体的高度共定位。有人提出，多聚磷酸盐可能是不同生物体中细胞能量储存的替代物，以及在 AD 和 PD 中受影响的许多线粒体过程的调节中多聚磷酸盐的作用，包括蛋白质和钙稳态。在这里，我们对有关多聚磷酸盐在 AD 和 PD 中线粒体功能障碍中的作用的文献进行了全面的回顾和讨论。考虑到本综述中提出的数据，我们假设多聚磷酸盐可能是对抗 AD 和 PD 中线粒体功能障碍的有效、创新和合理的药理学靶点。然而，应该进行进一步的研究以更好地了解多聚磷酸盐在神经退行性变中的确切作用，以及聚合物的代谢以及不同长度的多聚磷酸盐对细胞和线粒体生理学的影响。
