The mitochondrial NAD transporter SLC25A51 is a modulator of beta cell senescence and type 2 diabetes

Nicotinamide adenine dinucleotide (NAD⁺) is an essential redox cofactor and signaling molecule linked to age-dependent metabolic decline, with its compartmentalization regulated by the mitochondrial carrier SLC25A51. The mechanisms contributing to declining NAD⁺levels during aging and the consequences of altered NAD⁺homeostasis across tissues are poorly understood. Here, we show that SLC25A51 is upregulated in aging and aging- associated conditions, particularly in senescent cells. In a mouse model of beta-cell senescence, upregulated SLC25A51 was associated with beta-cell identity loss, senescence progression, and a reduced NAD⁺/NADH ratio. SLC25A51 was elevated following p16^INK4a-, replicative-, irradiation-, and H₂O₂-induced senescence, with NRF2 implicated as a potential transcriptional regulator. Overexpression of SLC25A51, but not a transport-dead mutant, induced senescence factors, while its deletion prevented this effect. Beta-cell-specific deletion of SLC25A51 lowered p16^INK4alevels in pancreatic islets, circulating insulin, and glucose levels, improving insulin sensitivity and indicating its role in cellular senescence and the metabolic control of beta-cell function.