Cellular senescence induced by down-regulation of correlates with exon skipping of mitochondrial-related gene .

As the most prevalent type of alternative splicing in animal cells, exon skipping plays an important role in expanding the diversity of transcriptome and proteome, thereby participating in the regulation of diverse physiological and pathological processes such as development, aging, and cancer. Cellular senescence serving as an anti-cancer mechanism could also contribute to individual aging. Although the dynamic changes of exon skipping during cellular senescence were revealed, its biological consequence and upstream regulator remain poorly understood. Here, by using human foreskin fibroblasts (HFF) replicative senescence as a model, we discovered that splicing factor PTBP1 was an important contributor for global exon skipping events during senescence. Down-regulated expression of induced senescence-associated phenotypes and related mitochondrial functional changes. Mechanistically, PTBP1 binds to the third exon of mitochondrial complex I subunit coding gene and protects the exon from skipping. We further confirmed that exon skipping of correlates with and partially contributes to cellular senescence and related mitochondrial functional changes upon knockdown. Together, we revealed for the first time that mitochondrial-related gene is a new downstream target for PTBP1-regulated exon skipping to mediate cellular senescence and mitochondrial functional changes.