miR-146a impedes the anti-aging effect of AMPK via NAMPT suppression and NAD+/SIRT inactivation

• Published in: Signal transduction and targeted therapy Vol. 7; no. 1; p. 66
• Main Authors: Gong, Hui, Chen, Honghan, Xiao, Peng, Huang, Ning, Han, Xiaojuan, Zhang, Jian, Yang, Yu, Li, Tiepeng, Zhao, Tingting, Tai, Haoran, Xu, Weitong, Zhang, Gongchang, Gong, Chuhui, Yang, Ming, Tang, Xiaoqiang, Xiao, Hengyi
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 04-03-2022; Nature Publishing Group
• Subjects: 3' Untranslated Regions; 631/443/7; 631/80/509; Adenine; Aging; AMP-activated protein kinase; AMP-Activated Protein Kinases - genetics; Cancer Research; Cell Biology; Gene expression; Internal Medicine; Kinases; Medicine; Medicine & Public Health; Metformin; Metformin - pharmacology; MicroRNAs; MicroRNAs - genetics; MicroRNAs - metabolism; miRNA; Molecular modelling; NAD; NAD - metabolism; NF-κB protein; Nicotinamide phosphoribosyltransferase; Nicotinamide Phosphoribosyltransferase - genetics; Nicotinamide Phosphoribosyltransferase - metabolism; Oncology; Pathology; Phosphoribosyltransferase; Phosphorylation; Senescence; Sirtuins - genetics; Transcription
• ISSN: 2059-3635; 2095-9907; 2059-3635
• DOI: 10.1038/s41392-022-00886-3

Nicotinamide adenine dinucleotide (NAD
+
) is indispensable for the anti-aging activity of the sirtuin (SIRT) family enzymes. AMP-activated protein kinase (AMPK) upregulates NAD
+
synthesis and SIRT activity in a nicotinamide phosphoribosyltransferase (NAMPT)-dependent manner. However, the molecular mechanisms that affect AMPK-driven NAMPT expression and NAD
+
/SIRT activation remain unclear. In this study, we tried to identify senescence-associated microRNAs (miRNAs) that negatively regulate the cascade linking AMPK and NAMPT expression. miRNA-screening experiments showed that the expression of miR-146a increased in senescent cells but decreased following AMPK activation. Additionally, miR-146a overexpression weakened the metformin-mediated upregulation of NAMPT expression, NAD
+
synthesis, SIRT activity, and senescence protection, whereas treatment with the miR-146a inhibitor reversed this effect. Importantly, these findings were observed both in vitro and in vivo. Mechanistically, miR-146a directly targeted the 3′-UTR of
Nampt
mRNA to reduce the expression of NAMPT. AMPK activators metformin and 5-aminoimidazole-4-carboxamide (AICAR) hindered miR-146a expression at the transcriptional level by promoting IκB kinase (IKK) phosphorylation to attenuate nuclear factor-kappaB (NF-κB) activity. These findings identified a novel cascade that negatively regulates the NAD
+
/SIRT pathway by suppressing miR-146a-mediated NAMPT downregulation. Furthermore, our results showed that miR-146a impedes the anti-aging effect of AMPK. This mutual inhibitory relationship between miR-146a and AMPK enriches our understanding of the molecular connections between AMPK and SIRT and provides new insight into miRNA-mediated NAD
+
/SIRT regulation and an intervention point for the prevention of aging and age-related diseases.