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Cellular senescence induced by down-regulation of PTBP1 correlates with exon skipping of mitochondrial related gene NDUFV3

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 the regulation of diverse physiological and pathological processes such as development, aging and cancer. Cellular senescence serves 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 PTBP1 induced senescence-associated phenotypes and related mitochondrial functional changes. Mechanistically, PTBP1 binds to the third exon of mitochondrial complex I subunit coding gene NDUFV3 and protects the exon from skipping. We further confirmed that exon skipping of NDUFV3 correlates with and partially contributes to cellular senescence and related mitochondrial functional changes upon PTBP1 knockdown. Together, we revealed for the first time that mitochondrial related gene NDUFV3 is a new downstream target for PTBP1-regulated exon skipping to mediate cellular senescence and mitochondrial functional changes.

ORGANISM(S): Homo sapiens

PROVIDER: GSE266081 | GEO | 2024/05/18

REPOSITORIES: GEO

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Project description:DallePazze2014 - Cellular senescene-induced mitochondrial dysfunction This model is described in the article: Dynamic modelling of pathways to cellular senescence reveals strategies for targeted interventions. Dalle Pezze P, Nelson G, Otten EG, Korolchuk VI, Kirkwood TB, von Zglinicki T, Shanley DP. PLoS Comput. Biol. 2014 Aug; 10(8): e1003728 Abstract: Cellular senescence, a state of irreversible cell cycle arrest, is thought to help protect an organism from cancer, yet also contributes to ageing. The changes which occur in senescence are controlled by networks of multiple signalling and feedback pathways at the cellular level, and the interplay between these is difficult to predict and understand. To unravel the intrinsic challenges of understanding such a highly networked system, we have taken a systems biology approach to cellular senescence. We report a detailed analysis of senescence signalling via DNA damage, insulin-TOR, FoxO3a transcription factors, oxidative stress response, mitochondrial regulation and mitophagy. We show in silico and in vitro that inhibition of reactive oxygen species can prevent loss of mitochondrial membrane potential, whilst inhibition of mTOR shows a partial rescue of mitochondrial mass changes during establishment of senescence. Dual inhibition of ROS and mTOR in vitro confirmed computational model predictions that it was possible to further reduce senescence-induced mitochondrial dysfunction and DNA double-strand breaks. However, these interventions were unable to abrogate the senescence-induced mitochondrial dysfunction completely, and we identified decreased mitochondrial fission as the potential driving force for increased mitochondrial mass via prevention of mitophagy. Dynamic sensitivity analysis of the model showed the network stabilised at a new late state of cellular senescence. This was characterised by poor network sensitivity, high signalling noise, low cellular energy, high inflammation and permanent cell cycle arrest suggesting an unsatisfactory outcome for treatments aiming to delay or reverse cellular senescence at late time points. Combinatorial targeted interventions are therefore possible for intervening in the cellular pathway to senescence, but in the cases identified here, are only capable of delaying senescence onset. This model is hosted on BioModels Database and identified by: BIOMD0000000582. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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Cellular senescence induced by down-regulation of PTBP1 correlates with exon skipping of mitochondrial related gene NDUFV3

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