Medical College of Georgia, Augusta University, Augusta, GA 30912, USA.
University of Georgia, Athens, GA, USA.
Oxid Med Cell Longev. 2021 Jan 28;2021:6626484. doi: 10.1155/2021/6626484. eCollection 2021.
The aging process is associated with significant alterations in mitochondrial function. These changes in mitochondrial function are thought to involve increased production of reactive oxygen species (ROS), which over time contribute to cell death, senescence, tissue degeneration, and impaired tissue repair. The mitochondrial permeability transition pore (mPTP) is likely to play a critical role in these processes, as increased ROS activates mPTP opening, which further increases ROS production. Injury and inflammation are also thought to increase mPTP opening, and chronic, low-grade inflammation is a hallmark of aging. Nicotinamide adenine dinucleotide (NAD+) can suppress the frequency and duration of mPTP opening; however, NAD+ levels are known to decline with age, further stimulating mPTP opening and increasing ROS release. Research on neurodegenerative diseases, particularly on Parkinson's disease (PD) and Alzheimer's disease (AD), has uncovered significant findings regarding mPTP openings and aging. Parkinson's disease is associated with a reduction in mitochondrial complex I activity and increased oxidative damage of DNA, both of which are linked to mPTP opening and subsequent ROS release. Similarly, AD is associated with increased mPTP openings, as evidenced by amyloid-beta (A) interaction with the pore regulator cyclophilin D (CypD). Targeted therapies that can reduce the frequency and duration of mPTP opening may therefore have the potential to prevent age-related declines in cell and tissue function in various systems including the central nervous system.
衰老过程与线粒体功能的显著改变有关。线粒体功能的这些变化被认为涉及活性氧（ROS）产生的增加，随着时间的推移，ROS 会导致细胞死亡、衰老、组织退化和组织修复受损。线粒体通透性转换孔（mPTP）可能在这些过程中发挥关键作用，因为增加的 ROS 激活 mPTP 开放，进一步增加 ROS 产生。损伤和炎症也被认为会增加 mPTP 的开放，而慢性、低度炎症是衰老的标志。烟酰胺腺嘌呤二核苷酸（NAD+）可以抑制 mPTP 开放的频率和持续时间；然而，已知 NAD+水平随年龄的增长而下降，进一步刺激 mPTP 开放并增加 ROS 释放。对神经退行性疾病的研究，特别是帕金森病（PD）和阿尔茨海默病（AD），揭示了 mPTP 开放和衰老之间的重要发现。帕金森病与线粒体复合物 I 活性降低和 DNA 氧化损伤增加有关，这两者都与 mPTP 开放和随后的 ROS 释放有关。同样，AD 与 mPTP 开放增加有关，这可以通过淀粉样β（A）与孔调节剂亲环蛋白 D（CypD）相互作用来证明。因此，能够降低 mPTP 开放频率和持续时间的靶向治疗可能具有预防包括中枢神经系统在内的各种系统中与年龄相关的细胞和组织功能下降的潜力。
