The m7G methyltransferase METTL1 promotes acute kidney inflammation by disrupting mitochondrial function.

INTRODUCTION

RNA modifications regulate the progression of inflammatory diseases. However, the role of N7-methylguanosine (m7G) modification and its regulatory enzyme, methyltransferase-like 1 (METTL1), in inflammatory kidney diseases remains poorly understood. Here, we aimed to investigate the function and underlying mechanisms of METTL1-mediated m7G modification in acute kidney injury (AKI).

METHODS

Kidney tubular epithelial cell (TEC)-specific METTL1 conditional knockout mice were used to evaluate the functional role of METTL1 in multiple AKI mouse models (cisplatin, ischemia/reperfusion and cecal ligation/puncture). Additionally, kidney tissue was obtained from patients with AKI and from the non-tumor kidney tissue of patients with nephrectomy for kidney cancer. RNA sequencing and m7G-methylated RNA immunoprecipitation sequencing were performed to identify downstream targets and elucidate underlying mechanisms.

RESULTS

Both m7G modification and METTL1 expression were markedly upregulated in TECs from patients and mice with AKI. TEC-specific deletion of METTL1 significantly attenuated kidney injury and inflammation in the multiple AKI mouse models. Mechanistically, METTL1-mediated m7G modification enhanced the stability of the TEA domain transcription factor 2 (TEAD2) mRNA by the binding protein Quaking. Elevated TEAD2 impaired mitochondrial function by transcriptionally repressing medium-chain acyl-CoA dehydrogenase (ACADM), thereby amplifying proinflammatory responses. METTL1 knockdown mediated by tetrahedral framework DNA nanostructures, as well as pharmacological inhibition with AZD1080, a novel METTL1 inhibitor, effectively alleviated the severity of AKI in mice in prevention and therapeutic approaches.

CONCLUSIONS

Our findings suggest that targeting the METTL1/TEAD2/ACADM axis may represent a potential therapeutic strategy for inflammatory kidney diseases.