NADPH and Mitochondrial Quality Control as Targets for a Circadian-Based Fasting and Exercise Therapy for the Treatment of Parkinson’s Disease

Abstract

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.

Ketogenic interventions in mild cognitive impairment, Alzheimer's disease, and Parkinson's disease: A systematic review and critical appraisal

“…Based on limited preliminary data, it is possible that more potent formulations (and correspondingly higher circulating β-HB levels) may be needed to significantly influence motor features. It is also possible that multi-pronged interventional approaches (of which therapeutic ketosis may represent a single dimension) may be required to address the complexity of PD pathophysiology ( 50 ). This line of research currently supports a “C” (possibly effective) recommendation for non-motor symptoms and a “U” recommendation (data inadequate or conflicting) for motor symptoms in PD based on AAN criteria.…”

Multi-omics studies reveal ameliorating effects of physical exercise on neurodegenerative diseases

“…Higher exercise intensity seemed to have the opposite effect on improvement while shorter durations might have no significant effect. Different types of exercise attenuate the neurodegenerative disease through different pathways ( Curtis et al, 2022 ). Aerobic and anaerobic training are both important for the release of myokines to improve systemic homeostasis and decrease inflammation.…”

“…High-intensity interval training modulates the autonomic nervous system and heart rate by decreasing the activity of the parasympathetic system and increasing the activity of the sympathetic system. All of these changes could benefit patients with neurodegenerative diseases ( Curtis et al, 2022 ). Unfortunately, most of the current omics studies are steady-state aerobic exercises.…”

Oxidative Stress in Age-Related Neurodegenerative Diseases: An Overview of Recent Tools and Findings

“…The amounts and ratios of oxidized and reduced NAD(H) and NADP(H) affect biosynthetic capability and, subsequently, regulate cell proliferation [23][24][25]. While mitochondria are vital to the cell survival, aberrant mitochondrial homeostasis (the so-called dysfunctional mitochondrial quality control, including dysregulated mitophagy) has been implicated in the pathogenesis of neurodegenerative diseases, such as AD [26], PD [27] and HD [28], and it has, thus, been proposed as a promising therapeutic target [29].…”