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.
Several protective compounds or “exerkines” were increased more during exercise early in the active phase, including serum AMP and beta-aminoisobutyric acid (BAIBA); muscle αkg, kynurenine, and GABA; liver BAIBA, kynurenine, and kynurenate; and hypothalamic BAIBA . There was also increased muscle GSSG/GSH that occurred when exercise was carried out in the active phase. The more oxidized cellular environment following exercise in the active phase likely allows for more mitohormesis and ROS-induced Nrf2 activation several hours later, increasing NADPH levels and correcting the deficit. The most striking finding was the much greater global increase in 2-hydroxybutyrate (α-hydroxybutyrate) levels following active-phase exercise. In the same way that the pyruvate/lactate ratio is a marker of the cytoplasmic [NAD+]/[NADH] ratio due to the high activity of lactate dehydrogenase in most tissues , the 2-ketobutyrate/2-hydroxybutyrate ratio is also a global redox marker of the cytoplasmic [NAD+]/[NADH] ratio  due to 2-ketobutyrate and 2-hydroxybutyrate also serving as substrates for lactate dehydrogenase . The more reduced [NAD+]/[NADH] ratio directly following exercise early in the active phase is likely an important signal to induce cytoprotective gene expression and metabolic changes leading to the restoration of the normal redox state.
The decreased hepatic cytoplasmic [NADP+]/[NADPH] ratio that occurs during fasting may require glucagon  and may not occur after carbohydrate consumption in part due to insulin signaling. When insulin binds its receptor on the plasma membrane, a signaling cascade is initiated activating protein kinase AKT that phosphorylates ATP-citrate lyase (ACLY) serine 454 to activate the enzyme . Thus, the citrate that is exported from the mitochondrial matrix is diverted away from the citrate–αkg shuttle that uses IDH1 for NADPH synthesis to boost cytoplasmic NADPH levels, and instead it is routed to the citrate–malate or citrate–pyruvate shuttles that use ACLY for the synthesis of acetyl-CoA and oxaloacetate. Acetyl-CoA is largely used for NADPH-depleting fatty acid synthesis. The malate dehydrogenase 1 (MDH1) enzyme converts the generated oxaloacetate into malate, which can either be transported back into the mitochondrial matrix for the citrate–malate shuttle or converted to pyruvate by cytoplasmic ME1 with the concurrent reduction of NADP+ to NADPH as part of the citrate–pyruvate shuttle. The pyruvate is then transported back into the mitochondrial matrix.