Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA.
Seeds Scientific Performance Research, Spire Institute, Geneva, OH 44041, USA.
Cells. 2022 Aug 4;11(15):2416. doi: 10.3390/cells11152416.
Dysfunctional mitochondrial quality control (MQC) is implicated in the pathogenesis of Parkinson's disease (PD). The improper selection of mitochondria for mitophagy increases reactive oxygen species (ROS) levels and lowers ATP levels. The downstream effects include oxidative damage, failure to maintain proteostasis and ion gradients, and decreased NAD and NADPH levels, resulting in insufficient energy metabolism and neurotransmitter synthesis. A ketosis-based metabolic therapy that increases the levels of (R)-3-hydroxybutyrate (BHB) may reverse the dysfunctional MQC by partially replacing glucose as an energy source, by stimulating mitophagy, and by decreasing inflammation. Fasting can potentially raise cytoplasmic NADPH levels by increasing the mitochondrial export and cytoplasmic metabolism of ketone body-derived citrate that increases flux through isocitrate dehydrogenase 1 (IDH1). NADPH is an essential cofactor for nitric oxide synthase, and the nitric oxide synthesized can diffuse into the mitochondrial matrix and react with electron transport chain-synthesized superoxide to form peroxynitrite. Excessive superoxide and peroxynitrite production can cause the opening of the mitochondrial permeability transition pore (mPTP) to depolarize the mitochondria and activate PINK1-dependent mitophagy. Both fasting and exercise increase ketogenesis and increase the cellular NAD/NADH ratio, both of which are beneficial for neuronal metabolism. In addition, both fasting and exercise engage the adaptive cellular stress response signaling pathways that protect neurons against the oxidative and proteotoxic stress implicated in PD. Here, we discuss how intermittent fasting from the evening meal through to the next-day lunch together with morning exercise, when circadian NAD/NADH is most oxidized, circadian NADP/NADPH is most reduced, and circadian mitophagy gene expression is high, may slow the progression of PD.
功能失调的线粒体质量控制（MQC）与帕金森病（PD）的发病机制有关。线粒体自噬对线粒体的选择不当会增加活性氧（ROS）水平并降低 ATP 水平。下游效应包括氧化损伤、无法维持蛋白质平衡和离子梯度以及 NAD 和 NADPH 水平降低，导致能量代谢和神经递质合成不足。一种基于酮体的代谢疗法，通过增加（R）-3-羟基丁酸（BHB）的水平，可能通过部分替代葡萄糖作为能量来源、刺激线粒体自噬以及减少炎症来逆转功能失调的 MQC。禁食可以通过增加源自酮体的柠檬酸的线粒体输出和细胞质代谢来潜在地提高细胞质 NADPH 水平，从而增加异柠檬酸脱氢酶 1（IDH1）的通量。NADPH 是一氧化氮合酶的必需辅因子，合成的一氧化氮可以扩散到线粒体基质中，并与电子传递链合成的超氧化物反应形成过氧亚硝酸盐。过量的超氧化物和过氧亚硝酸盐的产生会导致线粒体通透性转换孔（mPTP）打开，使线粒体去极化并激活 PINK1 依赖性线粒体自噬。禁食和运动均可增加酮体生成并增加细胞 NAD/NADH 比值，这两者都有益于神经元代谢。此外，禁食和运动都参与适应性细胞应激反应信号通路，保护神经元免受与 PD 相关的氧化和蛋白毒性应激。在这里，我们讨论了从晚餐到第二天午餐的间歇性禁食与晨练相结合如何发挥作用，当昼夜节律 NAD/NADH 最氧化、昼夜节律 NADP/NADPH 最还原以及昼夜节律线粒体自噬基因表达水平最高时，可能会减缓 PD 的进展。
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