FTO stabilizes MIS12 and counteracts senescence

Zhang, Sheng; Wu, Zeming; Shi, Yue; Wang, Si; Ren, Jie; Yu, Zihui; Huang, D.H.; Ke, Yan; He, Yifang; Liu, Xiaoqian; Ji, Qianzhao; Liu, Beibei; Liu, Zunpeng; Qu, Jing; Liu, Guanghui; Ci, Weimin; Wang, Xiaoqun; Zhang, Weiqi

doi:10.1007/s13238-022-00914-6

Cited by 21 publications

(17 citation statements)

References 15 publications

(26 reference statements)

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“…Another study showed that knockdown of METTL3 led to accelerated senescence by upregulating the expression of polo-like kinase 1 (PLK1), a critical cell cycle modulator, in an m 6 A-dependent manner (Luo et al, 2021). Moreover, knockout of obesity-associated protein (FTO), one of the "erasers" of m 6 A, also accelerated hMPC senescence, and downregulation of FTO led to increased overall m 6 A levels during ovarian aging in mice (Jiang et al, 2021;Sun et al, 2021;Zhang et al, 2022c). Taken together, these studies demonstrate that deregulation of m 6 A modification represents a novel epi-transcriptional biomarker in aging, and more investigation of m 6 A dynamics at the genome-wide scale is required to reveal its potential impact on aging.…”

Section: Deregulated Rna Modificationsmentioning

confidence: 99%

Biomarkers of aging

Bao

Cao

Chen

et al. 2023

Sci. China Life Sci.

Self Cite

117

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Aging biomarkers are a combination of biological parameters to (i) assess age-related changes, (ii) track the physiological aging process, and (iii) predict the transition into a pathological status. Although a broad spectrum of aging biomarkers has been developed, their potential uses and limitations remain poorly characterized. An immediate goal of biomarkers is to help us answer the following three fundamental questions in aging research: How old are we? Why do we get old? And how can we age slower? This review aims to address this need. Here, we summarize our current knowledge of biomarkers developed for cellular, organ, and organismal levels of aging, comprising six pillars: physiological characteristics, medical imaging, histological features, cellular alterations, molecular changes, and secretory factors. To fulfill all these requisites, we propose that aging biomarkers should qualify for being specific, systemic, and clinically relevant. Supporting Information The supporting information is available online at 10.1007/s11427-023-2305-0. The supporting materials are published as submitted, without typesetting or editing. The responsibility for scientific accuracy and content remains entirely with the authors.

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Section: Deregulated Rna Modificationsmentioning

confidence: 99%

Biomarkers of aging

Bao

Cao

Chen

et al. 2023

Sci. China Life Sci.

Self Cite

117

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“…The PDI gene knockout was performed with the CRISPR/Cas9 genome editing system (Hu et al , 2020; Zhang et al , 2022a). In brief, the guide sequence targeting the exon 2 of the PDI gene was cloned into the pCAG‐mCherry‐gRNA vector (Addgene #87110).…”

Section: Methodsmentioning

confidence: 99%

Reducing oxidative protein folding alleviates senescence by minimizing ER‐to‐nucleus H₂O₂ release

Fang

Wang

et al. 2023

EMBO Reports

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Oxidative protein folding occurs in the endoplasmic reticulum (ER) to generate disulfide bonds, and the by‐product is hydrogen peroxide (H2O2). However, the relationship between oxidative protein folding and senescence remains uncharacterized. Here, we find that the protein disulfide isomerase (PDI), a key oxidoreductase that catalyzes oxidative protein folding, accumulated in aged human mesenchymal stem cells (hMSCs) and deletion of PDI alleviated hMSCs senescence. Mechanistically, knocking out PDI slows the rate of oxidative protein folding and decreases the leakage of ER‐derived H2O2 into the nucleus, thereby decreasing the expression of SERPINE1, which was identified as a key driver of cell senescence. Furthermore, we show that depletion of PDI alleviated senescence in various cell models of aging. Our findings reveal a previously unrecognized role of oxidative protein folding in promoting cell aging, providing a potential target for aging and aging‐related disease intervention.

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“…To generate FLAG-tagged 4E-BP1 and 3×FLAG-tagged 4E-BP1 expression plasmids, EIF4EBP1 cDNA was generated from EIF4EBP1 +/+ hMSCs via reverse-transcription (RT) PCR amplification and then cloned into the pLE4 empty vector (a kind gift from Dr. Tomoaki Hishida) using a NovoRec ® Plus One-Step PCR Cloning Kit (Novoprotein) according to the manufacturer’s instructions. For lenti-CRISPR/Cas9 mediated UQCRC2 knockout assay, sgRNA targeting UQCRC2 (sg- UQCRC2 ) was cloned into the lentiCRISPRv2 vector (Addgene, #52961) as previously described ( Zhang et al , 2022 ). shRNA targeting UQCRB (sh- UQCRB ) was cloned into the pLVTHM vector (Addgene, #12247).…”

Section: Methodsmentioning

confidence: 99%

4E-BP1 counteracts human mesenchymal stem cell senescence via maintaining mitochondrial homeostasis

et al. 2022

Protein &Amp; Cell

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Although the mTOR-4E-BP1 signaling pathway is implicated in aging and aging-related disorders, the role of 4E-BP1 in regulating human stem cell homeostasis remains largely unknown. Here, we report that the expression of 4E-BP1 decreases along with the senescence of human mesenchymal stem cells (hMSCs). Genetic inactivation of 4E-BP1 in hMSCs compromises mitochondrial respiration, increases mitochondrial reactive oxygen species (ROS) production, and accelerates cellular senescence. Mechanistically, the absence of 4E-BP1 destabilizes proteins in mitochondrial respiration complexes, especially several key subunits of the complex III including UQCRC2. Ectopic expression of 4E-BP1 attenuates mitochondrial abnormalities and alleviates cellular senescence in 4E-BP1-deficient hMSCs as well as in physiologically aged hMSCs. These findings together demonstrate that 4E-BP1 functions as a geroprotector to mitigate human stem cell senescence and maintain mitochondrial homeostasis, particularly for the mitochondrial respiration complex III, thus providing a new potential target to counteract human stem cell senescence.

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FTO stabilizes MIS12 and counteracts senescence

Cited by 21 publications

References 15 publications

Biomarkers of aging

Biomarkers of aging

Reducing oxidative protein folding alleviates senescence by minimizing ER‐to‐nucleus H₂O₂ release

4E-BP1 counteracts human mesenchymal stem cell senescence via maintaining mitochondrial homeostasis

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FTO stabilizes MIS12 and counteracts senescence

Cited by 21 publications

References 15 publications

Biomarkers of aging

Biomarkers of aging

Reducing oxidative protein folding alleviates senescence by minimizing ER‐to‐nucleus H2O2 release

4E-BP1 counteracts human mesenchymal stem cell senescence via maintaining mitochondrial homeostasis

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Reducing oxidative protein folding alleviates senescence by minimizing ER‐to‐nucleus H₂O₂ release