FTO inhibits UPRmt-induced apoptosis by activating JAK2/STAT3 pathway and reducing m6A level in adipocytes

Shen, Zhentong; Liu, Ping; Sun, Qian; Li, Yizhou; Acharya, Rabin Yu; Li, Xinjian; Sun, Cheng

doi:10.1007/s10495-021-01683-z

Cited by 33 publications

(19 citation statements)

References 46 publications

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“…In this respect, ATF5 silencing enabled mutant GFM1 cells’ survival in galactose and triggered an increase in the levels of other UPR mt -related proteins such as ATF4. This observation supports the relationship between ATF5 and cell survival [ 97 ]. The ability of ATF5 silencing to enhance cell survival was also observed in a previous study investigating the effect of proteasomal inhibition [ 96 ].…”

Section: Discussionsupporting

confidence: 89%

UPRmt activation improves pathological alterations in cellular models of mitochondrial diseases

Suárez-Rivero

Pastor-Maldonado

Povea-Cabello

et al. 2022

Orphanet J Rare Dis

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Background Mitochondrial diseases represent one of the most common groups of genetic diseases. With a prevalence greater than 1 in 5000 adults, such diseases still lack effective treatment. Current therapies are purely palliative and, in most cases, insufficient. Novel approaches to compensate and, if possible, revert mitochondrial dysfunction must be developed. Results In this study, we tackled the issue using as a model fibroblasts from a patient bearing a mutation in the GFM1 gene, which is involved in mitochondrial protein synthesis. Mutant GFM1 fibroblasts could not survive in galactose restrictive medium for more than 3 days, making them the perfect screening platform to test several compounds. Tetracycline enabled mutant GFM1 fibroblasts survival under nutritional stress. Here we demonstrate that tetracycline upregulates the mitochondrial Unfolded Protein Response (UPRmt), a compensatory pathway regulating mitochondrial proteostasis. We additionally report that activation of UPRmt improves mutant GFM1 cellular bioenergetics and partially restores mitochondrial protein expression. Conclusions Overall, we provide compelling evidence to propose the activation of intrinsic cellular compensatory mechanisms as promising therapeutic strategy for mitochondrial diseases.

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Section: Discussionsupporting

confidence: 89%

UPRmt activation improves pathological alterations in cellular models of mitochondrial diseases

Suárez-Rivero

Pastor-Maldonado

Povea-Cabello

et al. 2022

Orphanet J Rare Dis

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“… 12 , 13 The m6A modification is marked by “writers,” including Methyltransferase‐Like Protein 3 (Mettl3), Mettl14, and the associated protein Wilms' Tumor 1‐Associated Protein (WTAP), and is removed by “erasers,” such as fat mass and obesity‐associated protein (FTO) and AlkB Homolog 5 (ALKBH5). 14 , 15 , 16 The m6A modified RNA is recognized by “readers” to regulate gene expression. 17 , 18 Recent study finds that m6A modification levels of RNA are differentially regulated in atherosclerotic lesions.…”

Section: Introductionmentioning

confidence: 99%

Mettl3 promotes oxLDL‐mediated inflammation through activating STAT1 signaling

Huangfu

et al. 2021

Clinical Laboratory Analysis

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“…Overexpression of FTO in mice could significantly improve body weight and fat mass [43]. Betaine and cycloleucine were found to inhibit and promote FTO mRNA expression in 3T3-L1 cells, respectively [44]. The above results indicate that FTO is, to a certain extent, a downstream target gene of these two chemicals.…”

Section: Discussionmentioning

confidence: 87%

m6A demethylase FTO regulate CTNNB1 to promote adipogenesis of chicken preadipocyte

Huang

Wang

et al. 2022

J Animal Sci Biotechnol

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Background N6-methyladenosine (m6A) is an abundant post-transcriptional RNA modification that affects various biological processes. The fat mass and obesity-associated (FTO) protein, a demethylase encoded by the FTO gene, has been found to regulate adipocyte development in an m6A-dependent manner in multiple species. However, the effects of the m6A methylation and FTO demethylation functions on chicken adipogenesis remain unclear. This study aims to explore the association between m6A modification and chicken adipogenesis and the underlying mechanism by which FTO affects chicken preadipocyte development. Results The association between m6A modification and chicken lipogenesis was assessed by treating chicken preadipocytes with different doses of methyl donor betaine and methylation inhibitor cycloleucine. The results showed that betaine significantly increased methylation levels and inhibited lipogenesis, and the inverse effect was found in preadipocytes after cycloleucine treatment. Overexpression of FTO significantly inhibited m6A levels and promoted proliferation and differentiation of chicken preadipocytes. Silencing FTO showed opposite results. Mechanistically, FTO overexpression increased the expression of catenin beta 1 (CTNNB1) by improving RNA stability in an m6A-dependent manner, and we proved that FTO could directly target CTNNB1. Furthermore, CTNNB1 may be a positive regulator of adipogenesis in chicken preadipocytes. Conclusions m6A methylation of RNA was negatively associated with adipogenesis of chicken preadipocytes. FTO could regulate CTNNB1 expression in a demethylation manner to promote lipogenesis.

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FTO inhibits UPRmt-induced apoptosis by activating JAK2/STAT3 pathway and reducing m6A level in adipocytes

Cited by 33 publications

References 46 publications

UPRmt activation improves pathological alterations in cellular models of mitochondrial diseases

UPRmt activation improves pathological alterations in cellular models of mitochondrial diseases

Mettl3 promotes oxLDL‐mediated inflammation through activating STAT1 signaling

m6A demethylase FTO regulate CTNNB1 to promote adipogenesis of chicken preadipocyte

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