Nicotinamide mononucleotide combined with PJ-34 protects microglial cells from lipopolysaccharide-induced mitochondrial impairment through NMNAT3-PARP1 axis.

Abstract

Lipopolysaccharide (LPS) is known to induce cell injury and mitochondrial dysfunction, which are pivotal in neuroinflammation and related disorders. Recent studies have demonstrated the potential of nicotinamide mononucleotide (NMN) and poly(ADP-ribose) polymerase-1 (PARP1) inhibitors to enhance mitochondrial function. However, the underlying mechanisms have not been fully elucidated. This study investigates the impact of NMN in conjunction with PJ-34, a PARP1 inhibitor, on LPS-induced mitochondrial damage, focusing on nicotinamide mononucleotide adenylyl transferase 3 (NMNAT3) -PARP1 axis. The results showed that LPS treatment led to down-regulation of NMNAT3 (decreased 58.72% at 1 µM), up-regulation of PARP1 (enhanced 22.78% at 1 µM), thereby impairing mitophagy and mitochondrial function. The negative effects can be mitigated through supplementation with NMN and PJ-34. Specifically, compared to the LPS group, the expression of NMNAT3 increased by 63.29% and PARP1 decreased by 27.94% at a concentration of 400 µM NMN. Additionally, when 400 µM NMN was combined with 5 µM PJ-34, PARP1 expression decreased by 21.99%. Mechanistic studies reveal that NMN and PJ-34 counteracted the detrimental effects by promoting the binding of FoxO1 to the PINK1 promoter to activate the PINK1/Parkin mediated mitophagy pathway. Further experimental results demonstrate that the down-regulation of NMNAT3 can activate PARP1 and inhibit the initiation of autophagic processes. Consequently, targeting the NMNAT3-PARP1 signaling pathway holds promise for the development of novel therapeutic strategies to alleviate mitochondrial damage-related disorders.