A novel AluYb8 insertion-associated non-coding RNA, lncMUTYH, impairs mitochondrial function and dampens the M2-like polarization of macrophages.

An inverted insertion in the intron 15 ( variant) has been reported to be associated with reduced MUTYH1 expression and mitochondrial dysfunction with age. However, the underlying mechanism remains unknown. In this study, we identified a novel transcript associated with the variant, which revealed that this transcript is about 780 nucleotides in length with a poly-A tail, lacks protein-coding potential, referred to as lncMUTYH. The results from the reporter gene system confirmed that the lncMUTYH down-regulates MUTYH1 expression at the translational level. Site-directed mutagenesis on the 5'-terminal exon sequences of and lncMUTYH constructs revealed that lncMUTYH can act as a -regulator that depends on the partial base pairing between its exonized sequence and the 5'UTR of to impede MUTYH 1 expression. Furthermore, we have demonstrated a correlation between decreased mitochondrion-localized MUTYH1 caused by lncMUTYH and lowered levels of mitochondrial biological function indicators, such as mtDNA content, mitochondrial regulatory gene expression, oxygen consumption rate, ATP product, and mitochondrial respiratory capacity. Notably, we found that lncMUTYH inhibited the M2-like polarization of macrophages, and CD68/CD206-positive cell fractions were significantly lower in lncMUTYH ectopically expressing cells. The results confirmed that the -associated lncMUTYH, derived from an insertion mutation, acts as a trans-regulatory factor that inhibits the MUTYH1 protein expression, leading to a progressive mitochondrial dysfunction that may disrupt macrophage differentiation. In summary, lncMUTYH can contribute to -associated mitochondrial dysfunction with age and hamper the macrophage polarization process, potentially increasing the risk of developing age-related diseases.