M6A RNA Methylation-Mediated TUG1 Stability Maintains Mitochondrial Homeostasis during Kidney Aging by Epigenetically Regulating PGC1-α Expression

• DOI: 10.1089/ars.2024.0631
• Publication Date: 2024-08-13T06:19:13Z
• Authors: Yonghong Zhu; Bowen Yang; Suyun Chen; Guanqing Chen; Xiaobian Zeng; Hui Min; Li Xu

Aging is a significant risk factor for the increased incidence of acute kidney injury and chronic kidney disease, posing significant challenges to global public health. The role of N6-methyladenosine (m6A) in the development of chronic kidney disease has been reported, but the regulatory mechanism of m6A in kidney aging remains unclear. In this study, we identified a long non-coding RNA (lncRNA), called TUG1, which exhibited a significantly decreased level of m6A modification in human aged kidney through the m6A-lncRNA epitranscriptome microarray. Bioinformatics analysis and machine learning predicted that TUG1 formed potentially strong interaction with PGC1-α. RIP and ChIP analysis supported that TUG1 promoted proliferator-activated receptor γ coactivator-1α (PGC1-α) expression by directly interact with its TBE region, thereby impacting mitochondrial quality control, cellular senescence and renal fibrosis. Silencing the RNA m6A methylase METTL14 or the reader protein IGF2BP2 resulted in the weakened stability of LncRNA TUG1, contributing to an imbalance in mitochondrial quality control. Our study demonstrated that Our study demonstrated that the m6A modification and stability of TUG1 was mediated by METTL14 in an IGF2BP2-dependent manner, and modulate the mitochondrial homeostasis in kidney aging by direct targeting PGC-1α. These findings provide a new perspective on potential therapeutic targets for kidney aging.