DSpace Community: KAIST Graduate School Medical Science & EngineeringKAIST Graduate School Medical Science & Engineeringhttp://hdl.handle.net/10203/5222024-03-28T11:10:11Z2024-03-28T11:10:11ZMitochondrial matrix RTN4IP1/OPA10 is an oxidoreductase for coenzyme Q synthesisPark, IsaacKim, Kwang-eunKim, JeesooKim, Ae-KyeongBae, SubinJung, MinkyoChoi, JinhyukMishra, Pratyush KumarKim, Taek-MinKwak, ChulhwanKang, Myeong-GyunYoo, Chang-MoMun, Ji YoungLiu, Kwang-HyeonLee, Kyu-SunKim, Jong-SeoSuh, Jae MyoungRhee, Hyun-Woohttp://hdl.handle.net/10203/3182432024-02-23T19:00:32Z2024-02-01T00:00:00ZTitle: Mitochondrial matrix RTN4IP1/OPA10 is an oxidoreductase for coenzyme Q synthesis
Authors: Park, Isaac; Kim, Kwang-eun; Kim, Jeesoo; Kim, Ae-Kyeong; Bae, Subin; Jung, Minkyo; Choi, Jinhyuk; Mishra, Pratyush Kumar; Kim, Taek-Min; Kwak, Chulhwan; Kang, Myeong-Gyun; Yoo, Chang-Mo; Mun, Ji Young; Liu, Kwang-Hyeon; Lee, Kyu-Sun; Kim, Jong-Seo; Suh, Jae Myoung; Rhee, Hyun-Woo
Abstract: Targeting proximity-labeling enzymes to specific cellular locations is a viable strategy for profiling subcellular proteomes. Here, we generated transgenic mice (MAX-Tg) expressing a mitochondrial matrix-targeted ascorbate peroxidase. Comparative analysis of matrix proteomes from the muscle tissues showed differential enrichment of mitochondrial proteins. We found that reticulon 4-interacting protein 1 (RTN4IP1), also known as optic atrophy-10, is enriched in the mitochondrial matrix of muscle tissues and is an NADPH oxidoreductase. Interactome analysis and in vitro enzymatic assays revealed an essential role for RTN4IP1 in coenzyme Q (CoQ) biosynthesis by regulating the O-methylation activity of COQ3. Rtn4ip1-knockout myoblasts had markedly decreased CoQ9 levels and impaired cellular respiration. Furthermore, muscle-specific knockdown of dRtn4ip1 in flies resulted in impaired muscle function, which was reversed by dietary supplementation with soluble CoQ. Collectively, these results demonstrate that RTN4IP1 is a mitochondrial NAD(P)H oxidoreductase essential for supporting mitochondrial respiration activity in the muscle tissue. The development of a transgenic mouse line that expresses mitochondrial matrix-targeted APEX2 combined with proteome analysis identified RTN4IP1, which serves as an NAD(P)H oxidoreductase required for respiration and CoQ biosynthesis.2024-02-01T00:00:00ZCannabidiol Inhibits IgE-Mediated Mast Cell Degranulation and Anaphylaxis in MiceYang, XiaohuiLee, DohyeonKim, Hyun-WooPark, Byung-HyunLim, ChangjinBae, Eun Juhttp://hdl.handle.net/10203/3186132024-03-28T08:00:12Z2024-02-01T00:00:00ZTitle: Cannabidiol Inhibits IgE-Mediated Mast Cell Degranulation and Anaphylaxis in Mice
Authors: Yang, Xiaohui; Lee, Dohyeon; Kim, Hyun-Woo; Park, Byung-Hyun; Lim, Changjin; Bae, Eun Ju
Abstract: ScopeCannabidiol (CBD), the most abundant non-psychoactive constituent of the plant Cannabis sativa, is known to possess immune modulatory properties. This study investigates the effects of CBD on mast cell degranulation in human and mouse primary mast cells and passive cutaneous anaphylaxis in mice.Methods and resultsMouse bone marrow-derived mast cells and human cord-blood derived mast cells are generated. CBD suppressed antigen-stimulated mast cell degranulation in a concentration-dependent manner. Mechanistically, CBD inhibited both the phosphorylation of Fc epsilon RI downstream signaling molecules and calcium mobilization in mast cells, while exerting no effect on Fc epsilon RI expression and IgE binding to Fc epsilon RI. These suppressive effects are preserved in the mast cells that are depleted of type 1 (CB1) and type 2 (CB2) cannabinoid receptors, as well as in the presence of CB1 agonist, CB2 agonist, CB1 inverse agonist, and CB2 inverse agonist. CBD also inhibited the development of mast cells in a long-term culture. The intraperitoneal administration of CBD suppressed passive cutaneous anaphylaxis in mice as evidenced by a reduction in ear swelling and decrease in the number of degranulated mast cells.ConclusionBased on these results, the administration of CBD is a new therapeutic intervention in mast cell-associated anaphylactic diseases. The effects of cannabidiol (CBD), the most abundant non-psychotropic component of marijuana plant (Cannabis sativa) on mast cell degranulation are investigated using mouse and human mast cells. The results suggest that CBD suppresses mast cell degranulation by inhibiting the phosphorylation of Fc epsilon RI downstream signaling molecules and calcium mobilization. Consequently, CBD suppresses passive cutaneous anaphylaxis in mice.image2024-02-01T00:00:00ZGinsenoside F2 Restrains Hepatic Steatosis and Inflammation by Altering the Binding Affinity of Liver X Receptor CoregulatorsKim, KyuraeKim, Myung-HoKang, Ji InBaek, Jong-InJeon, Byeong-MinKim, Ho MinKim, Sun ChangJeong, Won-Ilhttp://hdl.handle.net/10203/3176192024-01-10T05:01:06Z2024-01-01T00:00:00ZTitle: Ginsenoside F2 Restrains Hepatic Steatosis and Inflammation by Altering the Binding Affinity of Liver X Receptor Coregulators
Authors: Kim, Kyurae; Kim, Myung-Ho; Kang, Ji In; Baek, Jong-In; Jeon, Byeong-Min; Kim, Ho Min; Kim, Sun Chang; Jeong, Won-Il
Abstract: Background: Ginsenoside F2 (GF2), the protopanaxadiol-type constituent in Panax ginseng, has been reported to attenuate metabolic dysfunction-associated steatotic liver disease (MASLD). However, the mechanism of action is not fully understood. Here, this study investigates the molecular mechanism by which GF2 regulates MASLD progression through liver X receptor (LXR). Methods: To demonstrate the effect of GF2 on LXR activity, computational modeling of protein-ligand binding, Time-resolved fluorescence resonance energy transfer (TR-FRET) assay for LXR cofactor recruitment, and luciferase reporter assay were performed. LXR agonist T0901317 was used for LXR activation in hepatocytes and macrophages. MASLD was induced by high-fat diet (HFD) feeding with or without GF2 administration in WT and LXRα−/− mice. Results: Computational modeling showed that GF2 had a high affinity with LXRα. LXRE-luciferase reporter assay with amino acid substitution at the predicted ligand binding site revealed that the S264 residue of LXRα was the crucial interaction site of GF2. TR-FRET assay demonstrated that GF2 suppressed LXRα activity by favoring the binding of corepressors to LXRα while inhibiting the accessibility of coactivators. In vitro, GF2 treatments reduced T0901317-induced fat accumulation and pro-inflammatory cytokine expression in hepatocytes and macrophages, respectively. Consistently, GF2 administration ameliorated hepatic steatohepatitis and improved glucose or insulin tolerance in WT but not in LXRα−/− mice. Conclusion: GF2 alters the binding affinities of LXRα coregulators, thereby interrupting hepatic steatosis and inflammation in macrophages. Therefore, we propose that GF2 might be a potential therapeutic agent for the intervention in patients with MASLD.2024-01-01T00:00:00ZAPP-C31: An Intracellular Promoter of Both Metal-Free and Metal-Bound Amyloid-β<sub>40</sub> Aggregation and Toxicity in Alzheimer's DiseaseNam, EunjuLin, YuxiPark, JiyongDo, HyunsuHan, JiyeonJeong, BohyeonPark, SubinLee, Da YongKim, MingeunHan, JinjuBaik, Mu-HyunLee, Young-HoLim, Mi Heehttp://hdl.handle.net/10203/3183892024-03-05T02:00:44Z2024-01-01T00:00:00ZTitle: APP-C31: An Intracellular Promoter of Both Metal-Free and Metal-Bound Amyloid-β<sub>40</sub> Aggregation and Toxicity in Alzheimer's Disease
Authors: Nam, Eunju; Lin, Yuxi; Park, Jiyong; Do, Hyunsu; Han, Jiyeon; Jeong, Bohyeon; Park, Subin; Lee, Da Yong; Kim, Mingeun; Han, Jinju; Baik, Mu-Hyun; Lee, Young-Ho; Lim, Mi Hee
Abstract: Intracellular C-terminal cleavage of the amyloid precursor protein (APP) is elevated in the brains of Alzheimer's disease (AD) patients and produces a peptide labeled APP-C31 that is suspected to be involved in the pathology of AD. But details about the role of APP-C31 in the development of the disease are not known. Here, this work reports that APP-C31 directly interacts with the N-terminal and self-recognition regions of amyloid-beta(40) (A beta(40)) to form transient adducts, which facilitates the aggregation of both metal-free and metal-bound A beta(40) peptides and aggravates their toxicity. Specifically, APP-C31 increases the perinuclear and intranuclear generation of large A beta(40) deposits and, consequently, damages the nucleus leading to apoptosis. The A beta(40)-induced degeneration of neurites and inflammation are also intensified by APP-C31 in human neurons and murine brains. This study demonstrates a new function of APP-C31 as an intracellular promoter of A beta(40) amyloidogenesis in both metal-free and metal-present environments, and may offer an interesting alternative target for developing treatments for AD that have not been considered thus far.2024-01-01T00:00:00Z