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TFEB orchestrates stress recovery and paves the way for senescence induction in human dermal fibroblasts

ABSTRACT: Cells experience oxidative stress and widespread cellular damage during stress-induced premature senescence (SIPS). Senescent cells are characterized by an increase in lysosomal content, which may contribute to mitigating cellular damage by promoting autophagy. This study investigates the dynamics of lysosomal quality control in human dermal fibroblasts (HDF), specifically examining lysosomal signaling pathways during oxidative stress-induced SIPS. Our results reveal distinct signaling responses between the initial stress phase and the ensuing senescent phenotype. During the stress phase, treatment with tBHP, which undermines the antioxidant response, results in an escalation of lysosomal damage. Increased ROS levels trigger activation of AMP-activated protein kinase (AMPK) and inactivation of Akt, leading to suppression of mammalian target of rapamycin (mTOR). Inactivation of mTOR during this phase facilitates the activation of transcription factor EB (TFEB), a key player in modulating ROS levels, enhancing autophagy, and enabling cellular survival. Interestingly, TFEB knockdown cells under stress exhibited increased apoptosis, highlighting the protective role of TFEB in the stress response. As cells enter senescence, TFEB activity, required for the autophagic damage repair becomes less critical. The decrease in ROS levels leads to the normalization of AMPK and Akt signaling, resulting in reactivation of mTOR. This reactivation of mTOR, which is critical for establishing the senescent state, mediates the inactivation of TFEB. Consequently, as damage decreases, TFEB activity decreases. Our results reveal a dynamic interplay between TFEB and mTOR, highlighting a critical role of TFEB in modulating cellular fate during the transition from stress response to senescence and postulates TFEB activation as a potential senomorphic treatment.

ORGANISM(S): Homo sapiens

PROVIDER: GSE290476 | GEO | 2025/03/02

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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TFEB orchestrates stress recovery and paves the way for senescence induction in human dermal fibroblasts

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