A single-atom-based Rubik's cube as an energy generator via boosted NAD+ production

Chondrocyte senescence has been recognized as a pivotal pathogenic mechanism in osteoarthritis (OA) progression. Elevating nicotinamide adenine dinucleotide (NAD+) levels constitutes a promising strategy for promoting energy metabolism. In this study, single-atom copper (Cu-SAC) supported on nitrogen (N)-doped carbon exhibits N-configuration-dependent NADH-oxidase mimicking activity, with pyridinic N contributing more prominently to catalytic activity than pyrrolic N. A cubic-structured Cu-SAC enriched with pyridinic N achieves superior efficacy in augmenting intracellular NAD+ levels relative to NAD+ precursor supplementation. Furthermore, Cu-SAC enhances chondrocyte energy production by upregulating glycolytic and tricarboxylic acid cycle flux, facilitating cartilage extracellular matrix synthesis. Cu-SAC administration attenuates chondrocyte senescence by enhancing the NAD+-dependent deacetylase activity of sirtuin 3, reduces knee joint degeneration, and slows the progression of post-traumatic OA. These findings highlight a promising strategy for enhancing mitochondrial energy metabolism, offering potential therapeutic value for aging and age-related disorders.