Somatic Miwi2 modulates mitochondrial function in airway multiciliated cells and exacerbates influenza pathogenesis

MIWI2, a P element-induced wimpy testes (PIWI) argonaute protein known for suppressing retrotransposons during male gonadogenesis, has an unexplored role in mammalian somatic cells. We identify MIWI2 multiciliated (M2MC) cells as a rare subset of airway multiciliated cells and investigate MIWI2's function in antiviral host defense. We analyzed transcriptomes from <i>Miwi2</i> heterozygous (<i>Miwi2</i> ^+/tom) and deficient (<i>Miwi2</i> ^tom/tom) mice following influenza A infection. During infection, <i>Miwi2</i> deficiency was associated with reduced mitochondrial and ribosomal gene expression in M2MC cells, increased mitochondrial reactive oxygen species (ROS) production and ADP/ATP ratios in multiciliated cells, and enhanced viral clearance and recovery. Additionally, <i>Miwi2</i>-expressing cells exhibited reduced levels of small RNAs derived from nuclear mitochondrial DNA. These findings reveal a previously unrecognized role for <i>Miwi2</i> in regulating small non-coding RNAs and mitochondrial oxidant production in somatic cells, indicating a function beyond its established germline activities. Our study identifies <i>Miwi2</i>/<i>Piwil4</i> as a potential factor influencing susceptibility to severe respiratory infections.