Mitochondrial fusion induced by transforming growth factor-β1 serves as a switch that governs the metabolic reprogramming during differentiation of regulatory T cells

Fang, Yulai; Zhang, Qin; Lv, Changjun; Guo, Yilei; He, Yue; Guo, Pengxiang; Wei, Zhifeng; Xia, Yufeng; Dai, Yue

doi:10.1016/j.redox.2023.102709

Cited by 6 publications

(4 citation statements)

References 43 publications

(46 reference statements)

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“…The activation of each of these signaling pathways has been considered as a strong etiology for tumor development and immune escape in previous studies ( 39 – 41 ); notably, the IL6/JAK/STAT3 signaling pathway has been reported to contribute to immunotherapy resistance ( 42 ). These results concur with the conclusions of Fang et al ( 43 ), Povero et al ( 44 ) and Zhang et al ( 38 ). Furthermore, regarding tumor growth, the KRAS, G2M checkpoint and EMT pathways, which contribute to tumor development and metastasis, were also found to be activated in the high WF score group.…”

Section: Discussionsupporting

confidence: 93%

Identification and validation of a fatty acid metabolism gene signature for the promotion of metastasis in liver cancer

Zhang,

Sun,

Jin

et al. 2023

Oncol Lett

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Metastasis is a fatal status for liver cancer, and the identification of an effective prediction model and promising therapeutic target is essential. Given the known relationship between fatty acid (FA) metabolism and the liver, the present study aimed to investigate dysregulation of genes associated with FA metabolism in liver cancer. Bioinformatics analyses were performed on data from patients with hepatocellular carcinoma (HCC) obtained from The Cancer Genome Atlas database using R software packages. Online public tools such as the Human Protein Atlas, Tumor Immune Single-Cell Hub and the University of Alabama at Birmingham Cancer Data Analysis portal were also utilized. Some essential results were further verified using in vitro experiments using HepG2 liver cancer cells. A signature consisting of three genes associated with the progression and prognosis of HCC and FA metabolism was identified. When samples were scored based on the expression of these genes and divided according to the median value, the higher score group showed a worse outcome and repressive immune microenvironment than the lower score group. Downstream pathways such as hypoxia, IL6/JAK/STAT3 and epithelial-mesenchymal transition were found to be significantly activated in the higher score group. As the core factor in the signature, mitochondrial ribosomal protein L35 (MRPL35) was found to be upregulated in HCC and to have certain impacts on the dysregulation of effective immunity. Further investigations and in vitro experiments indicated that MRPL35 facilitates the migration and invasion abilities of liver cancer, and the resistance of HCC to treatment. These findings have important implications regarding the characteristics and mechanisms of metastasis in liver cancer, and provide a promising signature based on FA metabolism-related genes that may be used to predict outcomes and explored as a novel therapeutic target in liver cancer.

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Section: Discussionsupporting

confidence: 93%

Identification and validation of a fatty acid metabolism gene signature for the promotion of metastasis in liver cancer

Zhang,

Sun,

Jin

et al. 2023

Oncol Lett

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“…These results suggest that collagens, which are the most abundant proteins in the ECM, and other heat sensitive ECM components including growth factors may have a reduced role in the overall cardiac functional while affecting mitochondrial structure by either promoting mitochondrial fusion or inhibiting mitochondrial fission. Growth factors found in the human heart ECM, namely FGF19, TGFb and PDGF, [35], were shown to increase mitochondrial biogenesis and fusion in various cells [53][54][55]. Alternatively, while the exact connection between ECM structural proteins (i.e., collagen-I, fibronectin and vitronectin) and cardiolipin is not completely understood, cardiolipin, a mitochondria-exclusive phospholipid responsible for both mitochondria fusion and fission [56], was reported to inhibit cell attachment to these ECM proteins [57].…”

Section: Discussionmentioning

confidence: 99%

Adult Human Heart ECM Improves Human iPSC-CM Function via Mitochondrial and Metabolic Maturation

Ozcebe,

Tristan,

Zorlutuna

2023

Preprint

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Myocardial infarction can lead to the loss of billions of cardiomyocytes, and while cell-based therapies are a promising option, the immature nature of in vitro-generated human induced pluripotent stem cell (iPSC)-derived cardiomyocytes (iCMs) is a significant roadblock to their development. Through the years, various approaches have emerged to improve iCM maturation, yet none could fully recapitulate the complexity of cardiac development and were not enough to achieve full cardiac maturityin vitro.Cardiac differentiation occurs at the early stages of development in a highly dynamic environment. Although significantly improved over the past two decades, small molecule-based iPSC differentiation protocols don’t go beyond producing high purity fetal iCMs. Recently adult extracellular matrix (ECM) was shown to retain tissue memory and has shown some success in driving tissue-specific differentiation in unspecified cells in various organ systems. Therefore, here, we first characterized the adult human heart left ventricle components. We then investigated the effect of adult human heart-derived ECM on iPSC cardiac differentiation and subsequent maturation. By preconditioning iPSCs with ECM, we tested whether creating a cardiac environment around iPSCs would drive them toward cardiac fate before small molecule mediated differentiation. Ultimately, we investigated ECM components that might be responsible for the observed effects.We identified critical glycoproteins and proteoglycans involved in early cardiac development in the adult heart ECM. Namely, adult ECM had extracellular galactin-1, fibronectin, fibrillins, and basement-membrane-specific heparan-sulfate proteoglycan (HSPG), which have been implicated in normal heart development and associated with various embryonic developmental processes.Relatedly, we showed that preconditioning iPSCs with adult ECM resulted in enhanced cardiac differentiation, yielding iCMs with higher functional maturity. Further investigation revealed that a more developed mitochondrial network and coverage as well as enhanced metabolic maturity and a shift towards a more energetic profile allowed the observed functional enhancement in ECM pretreated iCMs.These findings demonstrate the potential of using cardiac ECM for promoting iCM maturation and suggest a promising strategy for improving the development of iCM-based therapies and in vitro cardiac disease modeling and drug screening studies. Upon manipulating ECM, such as heat denaturation and sonication to eliminate protein components and release ECM bound vesicle contents, respectively, we concluded that the beneficial effects that we observed are not solely due to the ECM proteins, and might be related to the decorative units attached to them.

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“… 272 During differentiation of Treg cells, fusion of mitochondria triggered by transforming growth factor-beta1 (TGFβ1) is a checkpoint which directs reprogramming of metabolic processes. 273 , 274 PGC1α participates in mitochondrial biogenesis and mitochondrial dynamics. Its deficiency in Tregs display attenuated suppressive functions in vivo and in vitro.…”

Section: The Pathophysiology Of Mitochondrial Dynamicsmentioning

confidence: 99%

Mitochondrial dynamics in health and disease: mechanisms and potential targets

Chen,

Zhao,

2023

Sig Transduct Target Ther

119

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Mitochondria are organelles that are able to adjust and respond to different stressors and metabolic needs within a cell, showcasing their plasticity and dynamic nature. These abilities allow them to effectively coordinate various cellular functions. Mitochondrial dynamics refers to the changing process of fission, fusion, mitophagy and transport, which is crucial for optimal function in signal transduction and metabolism. An imbalance in mitochondrial dynamics can disrupt mitochondrial function, leading to abnormal cellular fate, and a range of diseases, including neurodegenerative disorders, metabolic diseases, cardiovascular diseases and cancers. Herein, we review the mechanism of mitochondrial dynamics, and its impacts on cellular function. We also delve into the changes that occur in mitochondrial dynamics during health and disease, and offer novel perspectives on how to target the modulation of mitochondrial dynamics.

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Mitochondrial fusion induced by transforming growth factor-β1 serves as a switch that governs the metabolic reprogramming during differentiation of regulatory T cells

Cited by 6 publications

References 43 publications

Identification and validation of a fatty acid metabolism gene signature for the promotion of metastasis in liver cancer

Identification and validation of a fatty acid metabolism gene signature for the promotion of metastasis in liver cancer

Adult Human Heart ECM Improves Human iPSC-CM Function via Mitochondrial and Metabolic Maturation

Mitochondrial dynamics in health and disease: mechanisms and potential targets

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