Mitostemness

Cuyàs, Elisabet; Verdura, Sara; Folguera-Blasco, Núria; Bastidas-Velez, Cristian; Martín, Ángel G.; Alarcón, Tomás; Menendez, Javier A.

doi:10.1080/15384101.2018.1467679

Cited by 17 publications

(16 citation statements)

References 96 publications

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“…It has been reported that high glucose alters the gene expression by methylation or acetylation of lysine residues on histone H3. A recent report showed the involvement of H3K36me2, H3K27me3, H3K9me2, and H3K23ac in metabolic disorder . We also show that there is increased K36 di‐methylation of histone H3 in HFD + low dose STZ‐induced diabetic conditions and this elevation was suppressed by l ‐Met‐S as well as metformin treatment.…”

Section: Discussionsupporting

confidence: 66%

Dietary Supplementation of Methyl Donor l‐Methionine Alters Epigenetic Modification in Type 2 Diabetes

Navik

Sheth

Kabeer

et al. 2019

Molecular Nutrition Food Res

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Scope The aim of the current study is to evaluate whether l‐methionine supplementation (l‐Met‐S) improves type 2 diabetes‐induced alterations in glucose and lipid metabolism by modulating one‐carbon metabolism and methylation status. Methods and Results Diabetes is induced in male Sprague–Dawley rats using high‐fat diet and low dose streptozotocin. At the end of study, various biochemical parameters, immunoblotting, qRT‐PCR and ChIP‐qPCR are performed. The first evidence that l‐Met‐S activates p‐AMPK and SIRT1, very similar to “metformin,” is provided. l‐Met‐S improves the altered key one‐carbon metabolites in diabetic rats by modulating methionine adenosyl transferase 1A and cystathione β synthase expression. qRT‐PCR shows that l‐Met‐S alleviates diabetes‐induced increase in Forkhead transcription factor 1 expression and thereby regulating genes involved in glucose (G6pc, Pdk4, Pklr) and lipid metabolism (Fasn). Interestingly, l‐Met‐S inhibits the increased expression of DNMT1 and also prevents methylation of histone H3K36me2 under diabetic condition. ChIP assay shows that persistent increase in abundance of histone H3K36me2 on the promoter region of FOXO1 in diabetic rats and it is recovered by l‐Met‐S. Conclusion The first evidence that dietary supplementation of l‐Met prevents diabetes‐induced epigenetic alterations and regulating methionine levels can be therapeutically exploited for the treatment of metabolic diseases is provided.

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Section: Discussionsupporting

confidence: 66%

Dietary Supplementation of Methyl Donor l‐Methionine Alters Epigenetic Modification in Type 2 Diabetes

Navik

Sheth

Kabeer

et al. 2019

Molecular Nutrition Food Res

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“…In addition, mitochondria have been shown to support the survival of dormant tumor cells after oncogene ablation, thus promoting disease relapse (32). Many of these actions attributed to mitochondria have been correlated with the impact that these organelles exert on the biology of CSCs (33). Several lines of evidence have suggested that mitochondria support stem cell traits, thus facilitating self-renewal and resistance to differentiation (2).…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial Fission Factor (MFF) Inhibits Mitochondrial Metabolism and Reduces Breast Cancer Stem Cell (CSC) Activity

et al. 2020

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Elevated mitochondrial biogenesis and metabolism represent key features of breast cancer stem cells (CSCs), whose propagation is conducive to disease onset and progression. Therefore, interfering with mitochondria biology and function may be regarded as a useful approach to eradicate CSCs. Here, we used the breast cancer cell line MCF7 as a model system to interrogate how mitochondrial fission contributes to the development of mitochondrial dysfunction toward the inhibition of metabolic flux and stemness. We generated an isogenic MCF7 cell line transduced with Mitochondrial Fission Factor (MCF7-MFF), which is primarily involved in mitochondrial fission. We evaluated the biochemical, molecular and functional properties of MCF7-MFF cells, as compared to control MCF7 cells transduced with the empty vector (MCF7-Control). We observed that MFF over-expression reduces both mitochondrial mass and activity, as evaluated using the mitochondrial probes MitroTracker Red and MitoTracker Orange, respectively. The analysis of metabolic flux using the Seahorse XFe96 revealed the inhibition of OXPHOS and glycolysis in MCF7-MFF cells, suggesting that increased mitochondrial fission may impair the biochemical properties of these organelles. Notably, CSCs activity, assessed by 3D-tumorsphere assays, was reduced in MCF7-MFF cells. A similar trend was observed for the activity of ALDH, a well-established marker of stemness. We conclude that enhanced mitochondrial fission may compromise CSCs propagation, through the impairment of mitochondrial function, possibly leading to a quiescent cell phenotype. Unbiased proteomic analysis revealed that proteins involved in mitochondrial dysfunction, oxidative stress-response, fatty acid metabolism and hypoxia signaling are among the most highly up-regulated in MCF7-MFF cells. Of note, integrated analysis of top regulatory networks obtained from unbiased proteomics in MCF7-MFF cells predicts that this cell phenotype activates signaling systems and effectors involved in the inhibition of cell survival and adhesion, together with the activation of specific breast cancer cell death programs. Overall, our study shows that unbalanced and abnormal Sánchez-Alvarez et al. MFF Reduces CSCs Activity activation of mitochondrial fission may drive the impairment of mitochondrial metabolic function, leading to inhibition of CSC propagation, and the activation of quiescence programs. Exploiting the potential of mitochondria to control pivotal events in tumor biology may, therefore, represent a useful tool to prevent disease progression.

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“…In addition, mitochondrial morphology and fission-fusion dynamics have been implicated as determinants of cellular differentiation states. Interestingly, increased mitochondrial fission is reported to be associated with proliferation and invasiveness of cancer cells and dedifferentiation of stem cells (57,58). Because increased PHB in mitochondria is predicted to suppress fission, it is possible that the enhanced proliferation and dedifferentiation of neuroblastoma cells expressing high levels of PHB are due to nonmitochondrial functions of the protein.…”

Section: Discussionmentioning

confidence: 99%

Prohibitin promotes dedifferentiation and is a potential therapeutic target in neuroblastoma

MacArthur¹,

Bei²,

García³

et al. 2019

JCI Insight

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Mitostemness

Cited by 17 publications

References 96 publications

Dietary Supplementation of Methyl Donor l‐Methionine Alters Epigenetic Modification in Type 2 Diabetes

Dietary Supplementation of Methyl Donor l‐Methionine Alters Epigenetic Modification in Type 2 Diabetes

Mitochondrial Fission Factor (MFF) Inhibits Mitochondrial Metabolism and Reduces Breast Cancer Stem Cell (CSC) Activity

Prohibitin promotes dedifferentiation and is a potential therapeutic target in neuroblastoma

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