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更新于：2025-05-07

DENR

更新于：2025-05-07

基本信息

别名

DENR、density regulated re-initiation and release factor、Density-regulated protein

+ [5]

简介

Translation regulator forming a complex with MCTS1 to promote translation reinitiation. Translation reinitiation is the process where the small ribosomal subunit remains attached to the mRNA following termination of translation of a regulatory upstream ORF (uORF), and resume scanning on the same mRNA molecule to initiate translation of a downstream ORF, usually the main ORF (mORF). The MCTS1/DENR complex is pivotal to two linked mechanisms essential for translation reinitiation. Firstly, the dissociation of deacylated tRNAs from post-termination 40S ribosomal complexes during ribosome recycling. Secondly, the recruitment in an EIF2-independent manner of aminoacylated initiator tRNA to P site of 40S ribosomes for a new round of translation. This regulatory mechanism governs the translation of more than 150 genes which translation reinitiation is MCTS1/DENR complex-dependent.

关联

项与 DENR 相关的药物

MDIVI-1

靶点

DENR

作用机制

DENR抑制剂

在研机构

University of Louisville

原研机构

University of Louisville

在研适应症

围手术期缺血 [+1]

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

ASHA-091

靶点

DENR x UTRN

作用机制

DENR抑制剂 [+1]

在研机构

Asha Therapeutics LLC

原研机构

Asha Therapeutics LLC

在研适应症

肌萎缩侧索硬化 [+3]

非在研适应症

慢性疲劳综合征 [+1]

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

MB-0481

靶点

DENR

作用机制

DENR抑制剂

在研机构

Mitobridge, Inc.

原研机构

Mitobridge, Inc.

在研适应症-

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 DENR 相关的临床结果

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100 项与 DENR 相关的转化医学

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0 项与 DENR 相关的专利（医药）

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991

项与 DENR 相关的文献（医药）

2025-12-01·Molecular Biology Reports

Unraveling cell death mechanisms in traumatic brain injury: dynamic roles of ferroptosis and necroptosis

Review

作者: Anash, Mohd ; Maparu, Kousik ; Singh, Shamsher

Traumatic brain injury (TBI) remains a major cause of mortality and long-term disability worldwide, with ferroptosis and necroptosis emerging as key drivers of secondary neuronal damage. Ferroptosis, characterized by iron-dependent lipid peroxidation and mitochondrial dysfunction, exacerbates oxidative stress and neuronal cell death. In parallel, necroptosis, mediated by receptor-interacting protein kinases (RIPK1 and RIPK3), amplifies inflammation through membrane rupture and the release of cellular components. Mitochondrial dynamics, involving fission and fusion processes, play a dual role in regulating these pathways. While mitochondrial fusion preserves cellular integrity and reduces oxidative stress, excessive mitochondrial fission driven by dynamin-related protein 1 (DRP1) accelerates necroptotic signaling and neuronal injury. This intricate interplay between ferroptosis, necroptosis, and mitochondrial dynamics highlights potential therapeutic targets. Modulating these pathways through tailored interventions could reduce neuronal damage, mitigate neuroinflammation, and improve functional outcomes in TBI patients. Advancing our understanding of these mechanisms is essential for developing precision therapies that address the complex pathology of traumatic brain injury.

2025-06-01·Biochemical Pharmacology

7′-Hydroxyl substituted xanthones from Gentianella acuta revert hepatic steatosis in obese diabetic mice through preserving mitochondrial homeostasis

Article

作者: Zhang, Yi ; Wang, Tao ; Yu, Haiyang ; Wang, Yadong ; Chen, Qian ; Liu, Mengyang ; Wu, Jiaqi ; Li, Jian

Mitochondrial dysfunction is a key contributor to the development and progression of metabolic dysfunction-associated steatotic liver disease (MASLD). Xanthones, bioactive flavonoids derived from various herbal medicines, are renowned for their anti-inflammatory, antioxidant, and anti-tumor properties. This study aimed to investigate the effects of xanthones isolated from Gentianella acuta on hepatic steatosis and the underlying mechanisms regulating mitochondrial function. We report that a xanthone fraction (400 mg/kg/day) effectively prevented obesity and hepatic steatosis in obese diabetic db/db mice in vivo. In vitro, xanthones inhibited lipid accumulation and mitochondrial dysfunction induced by high glucose (20 mM) and high palmitic acid (200 µM) in HepG2 cells. Mechanistically, norathyriol (NTR), a major in vivo metabolite of Gentianella acuta, inhibited the activity of dynamin-related protein 1 (Drp1), a protein associated with mitochondrial fission, and prevented its translocation from the cytoplasm to the mitochondria by inhibiting the orphan nuclear receptor (Nur77). Additionally, NTR increased the expression of the mitochondrial outer membrane protein FUN14 domain containing 1 (FUNDC1), which stimulated mitophagy to clear damaged or dysfunctional mitochondria under overnutrition conditions. We also discovered that reactive oxygen species (ROS) targeted FUNDC1, leading to mitochondrial damage, but this effect could be reversed by 7'-hydroxyl substituted xanthones. Collectively, 7'-hydroxyl substituted xanthones inhibited mitochondrial fission while promoting mitophagy, ultimately improving mitochondrial and liver function in diabetic hepatic steatosis. The modulation of mitochondrial function by 7'-hydroxyl substituted xanthones presents a novel approach for treating hepatic steatosis, particularly in diabetic conditions.

2025-06-01·Journal of Hazardous Materials

PFOS causes lysosomes-regulated mitochondrial fission through TRPML1-VDAC1 and oligomerization of MCU/ATP5J2

Article

作者: Sun, Xiance ; Hu, Lingli ; Li, Yu ; Liang, Peiyao ; Yao, Xiaofeng ; Feng, Ruzhen ; Qiu, Tianming ; Yang, Wei ; Zhang, Jingyuan ; Tian, Kefan ; Wang, Kejing

Perfluorooctane sulfonate (PFOS), a listed persistent organic pollutant, poses risks to human health and is closely linked to chronic metabolic diseases. Although the role of mitochondrial fission in these diseases has garnered attention, whether and how PFOS induces mitochondrial fission remains obscure. Here, we found that PFOS induced mitochondrial fission, as demonstrated by the fragmentation of mitochondria and the upregulation of dynamin-related protein 1 (DRP1), phospho-DRP1 and mitochondrial fission protein 1 (FIS1) in human hepatocytes MIHA and mice liver. Blocking the calcium transfer from lysosomes to mitochondria that was executed by transient receptor potential mucolipin 1 (TRPML1) of lysosomes and voltage-dependent anion channel 1 (VDAC1) of mitochondria, did not affect PFOS-induced mitochondrial fission. In contrast, knockdown of TRPML1 or VDAC1 reversed this process. Knockdown of mitochondrial calcium uniporter (MCU), rather than inhibiting its activity, effectively alleviated PFOS-induced mitochondrial fission. Additionally, PFOS increased MCU oligomers without affecting MCU monomer. Inhibiting autophagy reversed the MCU oligomerization. Further investigation unveiled the interactions of MCU with VDAC1, TRPML1, mitochondrial Fo complex subunit F2 (ATP5J2) and DRP1 in PFOS-exposed mice liver and MIHA cells. We also discovered that knockdown of ATP5J2 alleviated PFOS-induced mitochondrial fission. Ulteriorly, PFOS upregulated ATP5J2 that underwent oligomerization. Knockdown of MCU reversed the increase in ATP5J2. Our study uncovers the presence and molecular basics of lysosomes-regulated mitochondrial fission under PFOS exposure, explains the regulatory pathways on MCU and ATP5J2 oligomerization and their pivotal roles in mitochondrial fission, highlighting the involvement of mitochondrial fission in PFOS-related health risks.