Work

An m7G tRNA-derived fragment mediated thermogenic activation of brown adipose tissue through post-transcriptional repression of Uqcr10

Year: 2026

Type: article

Abstract: Obesity, diabetes, and related metabolic disorders have become global epidemics driven mainly by an imbalance between energy intake and energy expenditure. Brown adipose tissue (BAT), the principal site of non-shivering thermogenesis, can be activated to mitigate obesity and its metabolic sequelae. RNA modification is as important regulators of obesity. The N7-methylguanosine (m 7 G) modification broadly influences RNA stability, enhances translational efficiency, and helps determine cell fate. However, the specific mechanisms by which m 7 G regulates adipose thermogenesis remain unclear. Using untargeted metabolomics, we found that cold exposure activates thermogenic metabolism in BAT and that 7-Methylguanosine is elevated in thermogenically activated BAT. METTL1-mediated m 7 G modification correlates positively with adipose thermogenic activation. Loss of METTL1 reduces m 7 G levels and impairs adipocyte thermogenic capacity. At the same time, METTL1 deficiency alters tRNA cleavage patterns and generates regulatory tRNA-derived fragments that modulate gene expression. Overexpression of tRF-Lys-CTT, which derives from an m 7 G-modified tRNA, inhibits brown adipocyte differentiation and thermogenic activation; conversely, inhibiting tRF-Lys-CTT produces the opposite effects. Mechanistically, tRF-Lys-CTT associates with AGO2 to form a functional RISC complex that binds the 3'UTR of Uqcr10 mRNA and directly represses Uqcr10 post-transcriptionally. Under basal conditions, elevated tRF-Lys-CTT may constrain mitochondrial function by repressing Uqcr10 expression; upon cold stimulation, downregulation of tRF-Lys-CTT relieves this repression and promotes respiratory chain supercomplex assembly and UCP1-mediated thermogenesis. In summary, our study indicates that tRF-Lys-CTT functions as a post-transcriptional regulator of metabolism that suppresses thermogenesis, and provides new insights into the regulatory relationship among the METTL1/m 7 G/tRF axis and thermogenic control.

Source: Journal of Biological Chemistry

DOI: 10.1016/j.jbc.2026.113640