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The mitochondrial unfolded protein response and mitohormesis: a perspective on metabolic diseases
Yi, Hyon-Seung,Chang, Joon Young,Shong, Minho Bioscientifica Ltd 2018 Journal of molecular endocrinology Vol.61 No.3
<P>Mitochondria perform essential roles as crucial organelles for cellular and systemic energy homeostasis, and as signaling hubs, which coordinate nuclear transcriptional responses to the intra- and extra-cellular environment. Complex human diseases, including diabetes, obesity, fatty liver disease and aging-related degenerative diseases are associated with alterations in mitochondrial oxidative phosphorylation (OxPhos) function. However, a recent series of studies in animal models have revealed that an integrated response to tolerable mitochondrial stress appears to render cells less susceptible to subsequent aging processes and metabolic stresses, which is a key feature of mitohormesis. The mitochondrial unfolded protein response (UPR<SUP>mt</SUP>) is a central part of the mitohormetic response and is a retrograde signaling pathway, which utilizes the mitochondria-to-nucleus communication network. Our understanding of the UPR<SUP>mt</SUP> has contributed to elucidating the role of mitochondria in metabolic adaptation and lifespan regulation. In this review, we discuss and integrate recent data from the literature on the present status of mitochondrial OxPhos function in the development of metabolic diseases, relying on evidence from human and other animal studies, which points to alterations in mitochondrial function as a key factor in the regulation of metabolic diseases and conclude with a discussion on the specific roles of UPR<SUP>mt</SUP> and mitohormesis as a novel therapeutic strategy for the treatment of obesity and insulin resistance.</P>
Oncogenes, mitochondrial metabolism, and quality control in differentiated thyroid cancer
( Hyon-seung Yi ),( Joon Young Chang ),( Koon Soon Kim ),( Minho Shong ) 대한내과학회 2017 The Korean Journal of Internal Medicine Vol.32 No.5
Thyroid cancer is one of the most common malignancies of endocrine organs, and its incidence rate has increased steadily over the past several decades. Most differentiated thyroid tumors derived from thyroid epithelial cells exhibit slow-growing cancers, and patients with these tumors can achieve a good prognosis with surgical removal and radioiodine treatment. However, a small proportion of patients present with advanced thyroid cancer and are unusually resistant to current drug treatment modalities. Thyroid tumorigenesis is a complex process that is regulated by the activation of oncogenes, inactivation of tumor suppressors, and alterations in programmed cell death. Mitochondria play an essential role during tumor formation, progression, and metastasis of thyroid cancer. Recent studies have successfully observed the mitochondrial etiology of thyroid carcinogenesis. This review focuses on the recent progress in understanding the molecular mechanisms of thyroid cancer relating to altered mitochondrial metabolism.
LC : Cell Type-Dependent Role of Class III Alcohol Dehydrogenase during Hepatic Fibrogenesis in Mice
( Hyon Seung Yi ),( Young Sun Lee ),( Jin Seok Byun ),( Yang Gun Suh ),( Bin Gao ),( Won Il Jeong ) 대한간학회 2013 춘·추계 학술대회 (KASL) Vol.2013 No.1
Background and Aims: Hepatic stellate cells (HSCs) storing body retinols are currently considered as the one of the most important cells in the development of liver fibrosis. Several investigations have also revealed that retinol and its metabolites are associated with liver fibrosis. However, it is not clear yet why HSCs store retinols and what functions they have during hepatic fibrogenesis. Moreover, the critical enzymes responsible for retinol metabolism in HSCs and hepatic innate immune cells have not been elucidated. In this study, we identified the specific enzyme for retinol metabolism in HSCs and natural killer (NK) cells and also investigated the effects of the enzyme on HSCs and NK cells, respectively. Methods: Liver fibrosis was induced by bile duct ligation (BDL) or carbon tetrachloride (CCL4) treatment for 2 weeks. To inhibit retinol metabolism, 4 methylpyrazole (4-MP), an alcohol dehydrogenase (ADH) enzyme inhibitor, was administrated in mice. In vitro, HSCs and NK cells were isolated and cultured. Interference of ADH3 gene by siRNA and 4-MP treatment was used for assessing a role of ADH3 on HSCs and NK cells. Results: Inhibition of retinol metabolism by 4-MP treatment ameliorated liver fibrosis in both BDL and CCL4-induced liver fibrosis. In vitro, ADH3 expressed in isolated HSCs and NK cells and ADH3-mediated retinol metabolism was suppressed by 4-MP, leading to reduced expressions of fibrotic mediators in HSCs. Moreover, interference of ADH3 gene by siRNA inhibited activation and proliferation of HSCs. Furthermore, in co-culturing of liver NK cells with 4-day cultured HSCs, 4-MP treatment enhanced NK cell cytotoxicity against the activated HSCs via increasing interferon-gamma expression. Therefore, we found that the inhibition of ADH3-mediated retinol metabolism enhanced NK activation but suppressed HSCs inversely. Conclusions: Based on our findings, we could speculate that ADH3 is a critical enzyme for retinol metabolism in HSCs and NK cells. It plays a positive regulator in the activation of HSCs but a negative regulator in the activation of NK cells. Therefore, cell-type specific role of ADH3 may give rise to a new potential therapeutic target in liver fibrosis.
Assessment of Mitochondrial Function in Liver Research
( Hyon-seung Yi ) 대한간학회 2020 Postgraduate Courses (PG) Vol.2020 No.1
Hepatocytes have an eosinophilic cytoplasm upon hematoxylin-eosin staining, reflecting abundant mitochondria. Therefore, it is not surprising that mitochondrial dysfunction induces cellular damage and is associated with exacerbation of liver diseases. For instance, chronic alcohol consumption changes mitochondrial oxidative phosphorylation in the liver by suppressing the synthesis of respiratory complex proteins. Alcohol-mediated damage of mitochondrial DNA (mtDNA) also impairs cellular energy metabolism via enhanced formation of reactive oxygen species (ROS). Additionally, carbon tetrachloride (CCl4) reduces mitochondrial respiratory chain complex IV activity and depletes mtDNA in the liver. Moreover, the radicals produced by cytochrome P450 2E1-mediated CCl4 metabolism bind to mtDNA directly and also promote lipid peroxidation, which results in degradation of mtDNA. On the other hand, hepatic stellate cells, key players of liver fibrosis, can change into an activated state upon liver injury. Activation reflects the transdifferentiation from a quiescent vitamin A-rich cell to an activated stellate cell/myofibroblast. During this transdifferentiation, cellular energetics are altered from oxidative phosphorylation to glycolysis in hepatic stellate cells. Thus, understanding the changes in mitochondrial energetics is important in identifying the mechanism of liver fibrosis. Overall, this presentation will highlight assessment of mitochondrial function in hepatocytes as well as in hepatic stellate cells for figuring out hepatic physiology and pathology in the body.
강예은,Yi Hyon-Seung,Yeo Min-Kyung,Kim Jung Tae,Park Danbit,Jung Yewon,Kim Ok Soon,이성은,Kim Ji Min,Joung Kyong Hye,Lee Ju Hee,Ku Bon Jeong,Lee Mina,Kim Hyun Jin 대한의학회 2022 Journal of Korean medical science Vol.37 No.48
Background: Gestational diabetes mellitus (GDM) is the most common metabolic complication of pregnancy. To define the altered pathway in GDM placenta, we investigated the transcriptomic profiles from human placenta between GDM and controls. Methods: Clinical parameters and postpartum complications were reviewed in all participants. Differentially expressed canonical pathways were analyzed between the GDM and control groups based on transcriptomic analysis. CD4+ T, CD8+ T, and senescent T cell subsets were determined by flow cytometry based on staining for specific intracellular cytokines. Results: Gene ontology analysis revealed that the placenta of GDM revealed upregulation of diverse mitochondria or DNA replication related pathways and downregulation of T-cell immunity related pathways. The maternal placenta of the GDM group had a higher proportion of CD4+ T and CD8+ T cells than the control group. Interestingly, senescent CD4+ T cells tended to increase and CD8+ T cells were significantly increased in GDM compared to controls, along with increased programmed cell death-1 (CD274+ ) expression. Programmed death-ligand 1 expression in syncytotrophoblasts was also significantly increased in patients with GDM. Conclusion: This study demonstrated increased proinflammatory T cells, senescent T cells and immune-check point molecules in GDM placentas, suggesting that changes in senescent T cells and immune-escape signaling might be related to the pathophysiology of GDM.
Loss-of-function of IFT88 determines metabolic phenotypes in thyroid cancer
Lee, Junguee,Yi, Shinae,Won, Minho,Song, Young Shin,Yi, Hyon-Seung,Park, Young Joo,Park, Ki Cheol,Kim, Jung Tae,Chang, Joon Young,Lee, Min Joung,Sul, Hae Joung,Choi, Ji Eun,Kim, Koon Soon,Kero, Jukka Nature Publishing Group 2018 Oncogene Vol.37 No.32