A novel AluYb8 insertion-associated non-coding RNA, lncMUTYH, impairs mitochondrial function and dampens the M2-like polarization of macrophages
Creators: name: Dong, Gaochao
name: Yin, Xuewen
name: Liang, Yingkuan
name: Chen, Jingwen
name: Wang, Jie
name: Jiang, Feng
name: Wang, Chaochen
name: Guo, Wenwen
name: Wang, Yaping
Publisher: name: Taylor & Francis
Year: 2024
Subjects: subject: Biochemistry
subject: Medicine
subject: Cell Biology
subject: Genetics
subject: FOS: Biological sciences
subject: Molecular Biology
subject: Physiology
subject: Environmental Sciences not elsewhere classified
subject: Immunology
subject: FOS: Clinical medicine
subject: Biological Sciences not elsewhere classified
subject: Developmental Biology
subject: Cancer
subject: Infectious Diseases
subject: FOS: Health sciences
subject: Virology

description: An inverted <i>AluYb8</i> insertion in the <i>MUTYH</i> intron 15 (<i>AluYb8MUTYH</i> 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 <i>AluYb8MUTYH</i> 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 <i>α-MUTYH</i> and lncMUTYH constructs revealed that lncMUTYH can act as a <i>trans</i>-regulator that depends on the partial base pairing between its exonized <i>AluYb8</i> sequence and the 5′UTR of <i>α-MUTYH</i> 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 <i>AluYb8MUTYH</i>-associated lncMUTYH, derived from an <i>AluYb8</i> 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 <i>AluYb8MUTYH</i>-associated mitochondrial dysfunction with age and hamper the macrophage polarization process, potentially increasing the risk of developing age-related diseases. A novel non-coding RNA was identified derived from the <i>AluYb8</i> insertion in the <i>MUTYH</i> gene, namely lncMUTYH.LncMUTYH selectively decreased the MUTYH1 protein localized in mitochondrial, which is dependent on the sequence and orientation derived from <i>AluYb8</i> insertion.Overexpression of lncMUTYH dampens the mitochondrial function and M2-like polarization of macrophages, partly due to the suppression of the MUTYH1 protein. A novel non-coding RNA was identified derived from the <i>AluYb8</i> insertion in the <i>MUTYH</i> gene, namely lncMUTYH. LncMUTYH selectively decreased the MUTYH1 protein localized in mitochondrial, which is dependent on the sequence and orientation derived from <i>AluYb8</i> insertion. Overexpression of lncMUTYH dampens the mitochondrial function and M2-like polarization of macrophages, partly due to the suppression of the MUTYH1 protein.