Article
Biochemistry & Molecular Biology
Ruijie Liu, Jingjing Gu, Yilin Ye, Yuxin Zhang, Shaoxing Zhang, Qiange Lin, Shuying Yuan, Yanwen Chen, Xinrong Lu, Yongliang Tong, Shaoxian Lv, Li Chen, Guiqin Sun
Summary: This study used structure-based virtual analysis to screen for NGLY1 inhibitor candidates from natural compounds. Three natural compounds with significant inhibitory activity were identified, and their core structure was revealed. This finding could guide future drug development.
Article
Multidisciplinary Sciences
Ashutosh Pandey, Antonio Galeone, Seung Yeop Han, Benjamin A. Story, Gaia Consonni, William F. Mueller, Lars M. Steinmetz, Thomas Vaccari, Hamed Jafar-Nejad
Summary: Intestinal barrier dysfunction can cause inflammation and metabolic changes. However, the impact of gut bacteria versus non-bacterial insults on animal health in the context of barrier dysfunction is not well understood. This study establishes that loss of Drosophila N-glycanase 1 (Pngl) in a specific intestinal cell type leads to gut barrier defects, causing starvation and JNK overactivation. Loss of Pngl also results in immune and metabolic abnormalities, contributing to lethality.
NATURE COMMUNICATIONS
(2023)
Article
Chemistry, Medicinal
Ki-Sun Park, Hyungjun Kim, Hye Jin Kim, Kang-In Lee, Seo-Young Lee, Jieun Kim
Summary: In this study, it was demonstrated that Paeoniflorin (PNF) can inhibit TNF-α-induced skeletal muscle atrophy in postmenopausal women by restoring mitochondrial biosynthesis. PNF treatment restored differentiated myoblasts damaged by TNF-α and the diameter of atrophied myotubes. This mechanism was mediated through the regulation of estrogen receptor alpha (ERα) and the restoration of nuclear respiratory factor 1 (NRF1) and mitochondrial transcription factor A (TFAM).
Article
Cell Biology
May G. Akl, Lei Li, Raquel Baccetto, Sadhna Phanse, Qingzhou Zhang, Michael J. Trites, Sherin McDonald, Hiroyuki Aoki, Mohan Babu, Scott B. Widenmaier
Summary: Hepatic cholesterol overload promotes steatohepatitis, and insufficient understanding of liver stress defense impedes therapy development. In this study, the role of stress defense transcription factors NRF1 and NRF2 in counteracting cholesterol-linked liver stress is elucidated.
Article
Cell Biology
Gu Li, Bo Pan, Lifei Liu, Xiaohui Xu, Weian Zhao, Qiuhong Mou, Narae Hwang, Su Wol Chung, Xiaoli Liu, Jie Tian
Summary: Decompensated cardiac hypertrophy is often accompanied by mitochondrial dysfunction. This study investigated the role of HDAC1-mediated NRF1 histone deacetylation in cardiac hypertrophy. The administration of the HDAC1 inhibitor EGCG restored cardiac function, reduced heart/body weight and fibrosis, and increased mtDNA/nDNA ratio in hypertrophic hearts. In hypertrophic cardiomyocytes, EGCG attenuated cell hypertrophy and increased LC3B II(+)MitoTracker(+) puncta and mtDNA/nDNA ratio. Intervention with EGCG also upregulated NRF1 and PGC-1 alpha expression and enhanced their interaction. Furthermore, EGCG inhibited HDAC1 expression and increased acH3K9 or acH3K14 binding to the promoters of PGC-1 alpha and NRF1. Overall, this study suggests that EGCG prevents NRF1 reduction through inhibiting HDAC1-mediated histone deacetylation, and acetylation of NRF1 histone may be crucial for maintaining mitochondrial homeostasis in cardiac hypertrophy.
MOLECULAR AND CELLULAR BIOCHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Hiroto Hirayama, Tadashi Suzuki
Summary: Cytosolic peptide:N-glycanase (NGLY1 in mammals) is a conserved enzyme that plays a role in the deglycosylation of N-glycans attached to glycopeptide/glycoproteins. NGLY1 deficiency is an autosomal recessive disorder related to the NGLY1 gene, characterized by motor deficits and neurological problems. The intracerebroventricular administration of an adeno-associated virus 9 vector expressing human NGLY1 has been shown to partially restore motor functions in Ngly1(-/-) rats, suggesting a possible therapeutic intervention. Therefore, the development of robust assay methods for NGLY1 activity and the identification of NGLY1 deficiency-specific biomarkers are critical for early diagnosis and evaluation of treatment efficacy.
JOURNAL OF BIOCHEMISTRY
(2022)
Article
Cardiac & Cardiovascular Systems
Xiu-Long Wang, Rui-Xiang Sun, Dong-Xu Li, Zhi-Gang Chen, Xue-Fang Li, Si-Yu Sun, Fei Lin, Guo-An Zhao
Summary: This study aimed to investigate the effect of Salidroside on mitochondrial homeostasis after macrophage polarization and elucidate its possible mechanism against atherosclerosis. The results showed that Salidroside can inhibit M1 macrophage polarization, maintain mitochondrial homeostasis, and regulate the expression of proinflammatory factors and mitochondrial homeostasis-associated proteins.
JOURNAL OF CARDIOVASCULAR PHARMACOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Qing Tan, Xiaoqian Zhang, Shuxiang Li, Wenbin Liu, Jiaqi Yan, Siqi Wang, Feng Cui, Dan Li, Jun Li
Summary: Through genome-wide CRISPR-Cas9 knockout screening, researchers have identified DMT1 as a key regulator of mitochondrial membrane potential. DMT1 deficiency increases activity of mitochondrial complex I and decreases activity of complex III. This differential regulation leads to improved antioxidant capacity and suppression of ferroptosis. Additionally, alternative methods of increasing mitochondrial NAD+, such as NMN, show similar protective effects, suggesting potential therapeutic strategies for ferroptosis-related pathologies.
FREE RADICAL BIOLOGY AND MEDICINE
(2023)
Article
Gastroenterology & Hepatology
Andrew M. Shearer, Yanling Wang, Elizabeth K. Fletcher, Rajashree Rana, Emily S. Michael, Nga Nguyen, Manal F. Abdelmalek, Lidija Covic, Athan Kuliopulos
Summary: PAR2 expression increases in diabetes and NAFLD/NASH, suppressing glucose internalization and insulin signaling through a G(q)-dependent mechanism, making it a potential target for treating diabetes and NASH.
Article
Cell Biology
Gary Ruvkun, Nicolas Lehrbach
Summary: Nrf1, a member of the nuclear erythroid-2-like family of transcription factors, regulates stress-responsive gene expression in animals. Newly synthesized Nrf1 is first glycosylated in the endoplasmic reticulum (ER), then trafficked to the cytosol by ER-associated degradation (ERAD) machinery for rapid proteasomal degradation.
COLD SPRING HARBOR PERSPECTIVES IN BIOLOGY
(2023)
Review
Biochemistry & Molecular Biology
Yafang Wang, Na Li, Xin Zhang, Tiffany Horng
Summary: Mitochondria play a crucial role in regulating the activation, differentiation, and survival of macrophages and other immune cells. Changes in mitochondrial metabolism and various metabolites coordinate macrophage activation to distinct cellular states, clarifying the essential link between mitochondrial metabolism and immunity. Additionally, mitochondrial dysfunction and oxidative stress contribute to dysregulation of the inflammatory response in disease settings.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2021)
Article
Food Science & Technology
Myeong Joon Lee, Yeonoh Cho, Yujin Hwang, Youngheun Jo, Yeon-Gu Kim, Seung Hwan Lee, Jong Hun Lee
Summary: This study demonstrated that kaempferol can protect against mitochondrial damage and reduce the production of mitochondrial ROS in LPS-induced prostate organoids.
Article
Oncology
Ziyi Zhao, Yingwei Sun, Jing Tang, Yuting Yang, Xiaochao Xu
Summary: LRPPRC plays critical roles in regulating mitochondrial homeostasis, mitochondrial function, and tumorigenesis in osteosarcomas and osteosarcoma-derived CSCs, suggesting it may be a promising therapeutic target for osteosarcomas.
Article
Cell & Tissue Engineering
Nicole Baker, Steven Wade, Matthew Triolo, John Girgis, Damian Chwastek, Sarah Larrigan, Peter Feige, Ryo Fujita, Colin Crist, Michael A. Rudnicki, Yan Burelle, Mireille Khacho
Summary: Physiological changes in mitochondrial shape play a crucial role in regulating the quiescent state and activation potential of adult stem cells. Mitochondrial fragmentation promotes the exit from deep quiescence, while loss of the mitochondrial fusion protein OPA1 leads to premature activation and depletion of stem cells.
Article
Pharmacology & Pharmacy
John J. W. Han, Carolyn D. Nguyen, Julianna P. Thrasher, Anna DeGuzman, Jefferson Y. Chan
Summary: The Nrf1 transcription factor plays a crucial role in modulating cellular stress response against patulin cytotoxicity. Loss of Nrf1 leads to increased sensitivity to patulin-induced cytotoxic effects, suggesting its potential as a target for therapeutic interventions against patulin toxicity.
Article
Immunology
Rajkumar Venkatadri, Vikram Sabapathy, Murat Dogan, Saleh Mohammad, Scott E. Harvey, Sean R. Simpson, Jason M. Grayson, Nan Yan, Fred W. Perrino, Rahul Sharma
Summary: The study reveals a Th1 bias and elevated Tfh cells and germinal center B cells in TREX1 D18N mice. Inhibiting Bcl6 can attenuate Tfh, germinal center, and Th1 responses and rescue TREX1 D18N mice from autoimmunity. These findings suggest that Tfh cells and germinal center B cells may serve as potential therapeutic targets for autoimmune diseases.
EUROPEAN JOURNAL OF IMMUNOLOGY
(2022)
Article
Immunology
Taisuke Ohto, Ahmed Abu Tayeh, Ryuta Nishikomori, Hiroto Abe, Kyota Hashimoto, Shiro Baba, Anahi-Paula Arias-Loza, Nobumasa Soda, Saya Satoh, Masashi Matsuda, Yusuke Iizuka, Takashi Kondo, Haruhiko Koseki, Nan Yan, Takahiro Higuchi, Takashi Fujita, Hiroki Kato
Summary: Mutations in the IFIH1 gene, which codes for the viral RNA sensor MDA5, have been found to be responsible for the development of myocarditis and nephritis. This study demonstrates that the production of type I interferons and chemokines from cardiomyocytes play a critical role in the development of myocarditis. Activated lymphocytes and autoantibodies exacerbate the pathogenesis but are not necessary for the onset of the disease.
JOURNAL OF AUTOIMMUNITY
(2022)
Review
Biochemistry & Molecular Biology
Jianjun Wu, Nan Yan
Summary: This review article summarizes the important role of stimulator of interferon genes (STING) in infection, autoimmune disease, and cancer. It focuses on the evolutionary origin and molecular mechanisms of STING-mediated interferon-independent activities. The article highlights that STING not only produces interferons, but also functions as a hub that converts multiple environmental cues into diverse cellular responses. These findings provide new insights for the clinical testing of STING agonists in cancer and the treatment of STING-associated human diseases.
JOURNAL OF MOLECULAR BIOLOGY
(2022)
Article
Immunology
Kun Yang, Jie Han, Jennifer G. Gill, Jason Y. Park, Meghana N. Sathe, Jyothsna Gattineni, Tracey Wright, Christian Wysocki, M. Teresa de la Morena, Nan Yan
Summary: Mutations in the SKIV2L gene cause severe B cell immunodeficiency in THES patients, indicating its crucial role in early B cell development.
SCIENCE IMMUNOLOGY
(2022)
Review
Immunology
Devon Jeltema, Kennady Abbott, Nan Yan
Summary: STING signaling plays a central role in multiple autoinflammatory and neurodegenerative diseases. This study reviews the influence of STING trafficking on signaling, proposes a model of tonic STING signaling, and discusses the emerging link between dysregulated STING trafficking and neurodegenerative disease.
JOURNAL OF EXPERIMENTAL MEDICINE
(2023)
Article
Immunology
Francine Lianne Emralino, Saya Satoh, Nobuhiro Sakai, Masamichi Takami, Fumihiko Takeuchi, Nan Yan, Frank Rutsch, Takashi Fujita, Hiroki Kato
Summary: Gain-of-function mutations in MDA5 lead to autoimmune IFNopathies. Mice with the SMS-associated mutation R822Q develop SMS-like symptoms and uncontrollable inflammation upon viral infection or vaccination. Interrupting IFN signaling or inhibiting JAK signaling can alleviate inflammation and improve mucosal damage, enabling survival.
JOURNAL OF IMMUNOLOGY
(2022)
Article
Multidisciplinary Sciences
Xintao Tu, Ting-Ting Chu, Devon Jeltema, Kennady Abbott, Kun Yang, Cong Xing, Jie Han, Nicole Dobbs, Nan Yan
Summary: This study reveals that interference with STING trafficking can trigger basal activation of interferon signaling, providing protection against infection. GCC2 and several RAB GTPases are identified as key regulators during the post-Golgi trafficking of STING. These findings suggest the potential of exploiting this mechanism for cancer immunotherapy.
NATURE COMMUNICATIONS
(2022)
Editorial Material
Biochemistry & Molecular Biology
Kun Yang, Nan Yan
Article
Biochemistry & Molecular Biology
Sheng-Tao Li, Hiroto Hirayama, Chengcheng Huang, Tsugiyo Matsuda, Ritsuko Oka, Takahiro Yamasaki, Daisuke Kohda, Tadashi Suzuki
Summary: It is known that oligosaccharyltransferase (OST) has hydrolytic activity toward dolichol-linked oligosaccharides, but the functional importance of this activity remains unknown. In this study, we found that the hydrolytic activity of OST is enhanced in yeast under conditions related to the biosynthesis of dolichol-linked oligosaccharides and ubiquitin ligase, but is canceled under conditions promoting protein unfolding. These results suggest a possible role of free N-glycans in protein folding.
Article
Biochemistry & Molecular Biology
Hiroto Hirayama, Yuriko Tachida, Junichi Seino, Tadashi Suzuki
Summary: The deficiency of cytosolic peptide N-glycanase (NGLY1) is a rare genetic disorder with common symptoms exhibited by patients, however, there is currently a lack of a reliable method to quantify NGLY1 activity.
Article
Biochemistry & Molecular Biology
Chengcheng Huang, Junichi Seino, Haruhiko Fujihira, Keiko Sato, Reiko Fujinawa, Zeynep Sumer-Bayraktar, Nozomi Ishii, Ichiro Matsuo, Shuichi Nakaya, Tadashi Suzuki
Summary: Recent studies have shown the presence of sialyl free N-glycans in animal sera, with a variety of neutral and sialylated FNGs. The formation mechanism of these FNGs remains unclear, and different species have varying ratios of Gn1-type sialyl FNGs. The discovery of small sialylated glycans similar to milk oligosaccharides in sera indicates a complex mechanism behind the formation of free oligosaccharides.
Article
Medicine, Research & Experimental
Kun Yang, Jie Han, Mayumi Asada, Jennifer G. Gill, Jason Y. Park, Meghana N. Sathe, Jyothsna Gattineni, Tracey Wright, Christian A. Wysocki, M. Teresa de la Morena, Luis A. Garza, Nan Yan
Summary: Inborn errors of nucleic acid metabolism often cause aberrant activation of nucleic acid sensing pathways, leading to autoimmune or autoinflammatory diseases. This study demonstrates the physiological function of SKIV2L in mammals. Skiv2l deficiency disrupts the homeostasis of epidermis and T cells, resulting in skin inflammation and hair abnormality. SKIV2L loss activates the mTORC1 pathway and drives autoinflammatory disease.
JOURNAL OF CLINICAL INVESTIGATION
(2022)