# ATP and NAD+
Footnote †: This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([[https://creativecommons.org/licenses/py/4.0/](https://creativecommons.org/licenses/py/4.0/)]([https://creativecommons.org/licenses/py/4.0/](https://creativecommons.org/licenses/py/4.0/))). oxidative phosphorylation, which uses metabolites generated by the tricarboxylic acid cycle (TCA) driving ATP production through the electron transport system (ETS). The ETS produces the proton gradient across the inner mitochondrial membrane used to generate ATP [6]. Mitochondria play an important role in regulating cellular stress and adaptive signaling through modulation of cell redox and metabolite homeostasis [7]. Mitochondrial complex I deficiency in PD has been well-described for over three decades [4; 8]. An age-related decline was observed in complexes I and IV activity from postmortem brains of individuals with PD and Alzheimer's disease (AD), with less robust evidence supporting deficits in major depressive disorder, bipolar disorder, and schizophrenia [9]. Defects in complex I of the ETS appear to be especially associated with PD and PD-like symptoms in animal models. For example, tetonene, a complex I inhibitor, is used to create rodent models of PD in the lab. Rotenone causes the accumulation of Lewy bodies in the nigrostriatal system and clinical features of parkinsonism [10]. Mitochondrial dysfunction, especially at complex I, is now understood to be central to PD pathophysiology and improvement in cellular respiration has the potential to prevent neuronal loss and improve clinical outcomes [5]. Magnetic resonance spectroscopy (MRS) is a noninvasive method of measuring cellular energy metabolism in vivo in a range of human tissues, including brain and muscle. MRS uses phosphorus (\({}^{31}\)P) to determine mitochondrial ATP production as well as basal metabolic states in skeletal muscle [11; 12; 13; 14]. Using \({}^{31}\)P MRS, putamen and midbrain ATP have been shown to be decreased in individuals across PD stages, but less is known about skeletal muscle mitochondrial function in PD [15]. A 1994 study of finger flexor muscles of seven patients with PD was unable to demonstrate a difference in cellular energetics when compared to eleven healthy controls [16]. In skeletal muscle, the rate of recovery of phosphocreatine (PCr) can be used to calculate the maximum rate of mitochondrial ATP production (ATPmax). In human skeletal muscle, ATPmax is correlated with mitochondrial content and maximum in vitro respiration and thus provides a non-invasive measure of mitochondrial capacity [17; 18]. This approach has been used to demonstrate declines in skeletal muscle ATPmax in aging skeletal muscle and in other chronic disease conditions [18; 19; 20]. Nicotinamide adenine dinucleotide (NAD) is a coenzyme consisting of two nucleotides joined through a diphosphate bridge; it exists in two forms, oxidized (NAD) and reduced (NADH). NAD is an oxidizing agent, able to accept electrons from other molecules in the cell. NAD can be synthesized endogenously from dietary niacin and recycled as part of the salvage pathway. The NAD\({}^{+}\)/NADH ratio is essential to maintaining redox balance of the cell, and reduced concentrations of NAD are linked to poor metabolic health in aging and chronic diseases [21; 22]. Elevating NAD levels by targeted supplementation has improved health and reversed pathology in animal models of disease [23; 24], and NAD enhancing supplements are currently being tested in clinical trials for multiple human conditions [25; 26; 27]. The therapeutic use of NAD+ precursors, such as nicotinamide riboside (NR), as a therapeutic target to compensate for deficits in complex I, is particularly appealing in PD [28]. NR was shown to prevent neuronal cell loss in patient-derived cell lines and Drosophila models of GBA-related PD [29]. NADPARK, a hallmark translational study, recently showed viability for NR as a potential therapeutic strategy in humans with PD [30].