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由 下调诱导的细胞衰老与线粒体相关基因的外显子跳跃相关。 （注：原文中“down-regulation of ”和“mitochondrial-related gene ”处有缺失信息）

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

作者信息

Yang Yu, Wen Haimei, Li Yuxin, Zeng Xin, Wei Gang, Gu Zhenglong, Ni Ting

机构信息

Center for Mitochondrial Genetics and Health Research, Greater Bay Area Institute of Precision Medicine (Guangzhou), Fudan University, Guangzhou 511400, China.

Collaborative Innovation Center of Genetics and Development, Human Phenome Institute, School of Life Sciences, Fudan University, Shanghai 200438, China.

出版信息

Life Med. 2024 May 3;3(2):lnae021. doi: 10.1093/lifemedi/lnae021. eCollection 2024 Apr.

DOI:10.1093/lifemedi/lnae021
PMID:39872664
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11749709/
Abstract

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.

摘要

作为动物细胞中最普遍的可变剪接类型，外显子跳跃在扩大转录组和蛋白质组的多样性方面发挥着重要作用，从而参与调控发育、衰老和癌症等多种生理和病理过程。细胞衰老作为一种抗癌机制，也可能导致个体衰老。尽管已揭示了细胞衰老过程中外显子跳跃的动态变化，但其生物学后果和上游调节因子仍知之甚少。在这里，我们以人包皮成纤维细胞（HFF）复制性衰老为模型，发现剪接因子PTBP1是衰老过程中全局外显子跳跃事件的重要促成因素。PTBP1表达下调诱导衰老相关表型和相关线粒体功能变化。机制上，PTBP1与线粒体复合物I亚基编码基因的第三个外显子结合，保护该外显子不被跳跃。我们进一步证实，敲低PTBP1后，该基因的外显子跳跃与细胞衰老及相关线粒体功能变化相关，并部分促成这些变化。总之，我们首次揭示线粒体相关基因是PTBP1调控的外显子跳跃的新下游靶点，以介导细胞衰老和线粒体功能变化。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/758a/11749709/2a6f51cea8e2/lnae021_fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/758a/11749709/ef645bab1581/lnae021_fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/758a/11749709/4d95518739bf/lnae021_fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/758a/11749709/bc61ac5ad53e/lnae021_fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/758a/11749709/e1b43bf0ea2b/lnae021_fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/758a/11749709/8f1f5892c59a/lnae021_fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/758a/11749709/577d3cfa54c5/lnae021_fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/758a/11749709/2a6f51cea8e2/lnae021_fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/758a/11749709/ef645bab1581/lnae021_fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/758a/11749709/4d95518739bf/lnae021_fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/758a/11749709/bc61ac5ad53e/lnae021_fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/758a/11749709/e1b43bf0ea2b/lnae021_fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/758a/11749709/8f1f5892c59a/lnae021_fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/758a/11749709/577d3cfa54c5/lnae021_fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/758a/11749709/2a6f51cea8e2/lnae021_fig7.jpg

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