Emerging therapeutic roles for NAD⁺ metabolism in mitochondrial and age‑related disorders
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Nicotinamide adenine dinucleotide (NAD⁺) is a central metabolic cofactor in eukaryotic cells that plays a critical role in regulating cellular metabolism and energy homeostasis. NAD⁺ in its reduced form (i.e. NADH) serves as the primary electron donor in mitochondrial respiratory chain, which involves adenosine triphosphate production by oxidative phosphorylation. The NAD⁺/NADH ratio also regulates the activity of various metabolic pathway enzymes such as those involved in glycolysis, Kreb’s cycle, and fatty acid oxidation. Intracellular NAD⁺ is synthesized de novo from l-tryptophan, although its main source of synthesis is through salvage pathways from dietary niacin as precursors. NAD⁺ is utilized by various proteins including sirtuins, poly ADP-ribose polymerases (PARPs) and cyclic ADP-ribose synthases. The NAD⁺ pool is thus set by a critical balance between NAD⁺ biosynthetic and NAD⁺ consuming pathways. Raising cellular NAD⁺ content by inducing its biosynthesis or inhibiting the activity of PARP and cADP-ribose synthases via genetic or pharmacological means lead to sirtuins activation. Sirtuins modulate distinct metabolic, energetic and stress response pathways, and through their activation, NAD⁺ directly links the cellular redox state with signaling and transcriptional events. NAD⁺ levels decline with mitochondrial dysfunction and reduced NAD⁺/NADH ratio is implicated in mitochondrial disorders, various age-related pathologies as well as during aging. Here, I will provide an overview of the current knowledge on NAD⁺ metabolism including its biosynthesis, utilization, compartmentalization and role in the regulation of metabolic homoeostasis. I will further discuss how augmenting intracellular NAD⁺ content increases oxidative metabolism to prevent bioenergetic and functional decline in multiple models of mitochondrial diseases and age-related disorders, and how this knowledge could be translated to the clinic for human relevance.