The Crucial Role of NAD⁺ in MitochondrialMetabolic Regulation

Mitochondria are central organelles in cellular metabolism, orchestrating energy production, biosynthetic pathways, and signaling networks. Nicotinamide adenine dinucleotide (NAD⁺) and its reduced form (NADH) are essential for mitochondrial metabolism, functioning both as redox coenzymes and as signaling agents that help regulate cellular balance.Thus, while its major role is in energy production, NAD+ is widely recognized as a metabolic cofactor and also serves as a substrate for various enzymes involved in cellular signaling, like sirtuins (SIRTs), poly (ADP-ribosyl) polymerases (PARPs), mono (ADP-ribosyl) transferases, and CD38. Sirtuins, a family of NAD⁺ dependent deacetylases, are critical in this regulatory network. SIRT3 removes acetyl groups from and enhances the activity of key enzymes that participate in fatty acid breakdown, the tricarboxylic acid (TCA) cycle, and the electron transport chain (etc), thereby enhancing mitochondrial efficiency and energy production. Mitochondrial NAD⁺ biosynthesis involves multiple pathways, including the de novo synthesis from tryptophan via the kynurenine and the salvage pathway, which recycles nicotinamide back to NAD⁺. Moreover, NAD⁺ concentrations influence mitochondrial dynamics such as fusion, fission, and mitophagy, which are essential for preserving mitochondrial integrity and function.NAD⁺ alsomodulates the balance between glycolysis and oxidative phosphorylation, influencing the metabolic flexibility of cells. During NAD⁺ depletion, mainly in metabolic disorders, cells often shift towards anaerobic glycolysis, reducing ATP production efficiency and increasing lactate production. This metabolic shift is associated with various pathophysiological conditions, including insulin resistance, neurodegeneration, and muscle wasting. This reviewexplores themultifaceted functions of NAD⁺ in regulating mitochondrialmetabolism. It highlights the underlying causes and pathological outcomes of disrupted NAD⁺ metabolism while exploring potential therapeutic targets and treatment strategies.