由二利胺脱酶激活诱导的NADH降解性压力导致cuproptosis
Si-Yi Zhang1, Xing-Hua Ren2, Cheng-Hong Zhang3
1Key Laboratory of Medical Cell Biology of Ministry of Education, Key Laboratory of Major Chronic Diseases of Nervous System of Liaoning Province, Health Sciences Institute of China Medical University, Shenyang, 110122, China.
Advanced science (Weinheim, Baden-Wurttemberg, Germany)
|December 5, 2025
概括
过度的铜积累会通过cuproptosis引起神经毒性,这是由NADH降解性压力驱动的细胞死亡途径. 准这种途径为铜过载神经系统疾病提供了新的治疗方法.
科学领域:
- 生物化学 生化学
- 神经科学是一个神经科学.
- 细胞生物学 细胞生物学
背景情况:
- 铜 (Cu) 对新陈代谢至关重要,但过量有毒,导致神经毒性.
- 目前用于铜过载的治疗方法很难控制神经症状.
- 型亡,一个依赖于Cu的细胞死亡途径,为神经毒性提供了新的见解.
研究的目的:
- 阐明线粒体呼吸和cuproptosis之间的机械联系.
- 调查NADH降解性压力在铜介导神经毒性的作用.
- 确定铜过载病理的潜在治疗点.
主要方法:
- 研究了二利胺脱酶 (DLD) 在铜毒性的作用.
- 分析了线粒体透性过渡孔 (mPTP) 开放和NADH转位.
- 评估了氨酸生物合成和能量压力对细胞死亡的影响.
- 利用SH-SY5Y神经母细胞瘤细胞进行实验验证.
主要成果:
- 过多的铜和性线粒体pH值激活DLD,导致NADH积累.
- 铜诱导mPTP开放,导致细胞质NADH减小压力.
- 异常的精氨酸生物合成和ATP耗尽是NADH减小压力的结果.
- 药理上抑制DLD,mPTP, purin合成或能量压力可以从铜诱导的死亡中拯救细胞.
结论:
- 质亡是一种新型的细胞死亡途径,依赖于NADH减小压力.
- 过多的铜会通过降低NADH的压力和能量耗尽引发神经毒性.
- 准DLD,mPTP, purin生物合成或能量压力为与铜过载相关的神经疾病提供了治疗机会.
相关概念视频
01:32Export of Misfolded Proteins out of the ER
5.0K
After folding, the ER assesses the quality of secretory and membrane proteins. The correctly folded proteins are cleared by the calnexin cycle for transport to their final destination, while misfolded proteins are held back in the ER lumen. The ER chaperones attempt to unfold and refold the misfolded proteins but sometimes fail to achieve the correct native conformation. Such terminally misfolded proteins are then exported to the cytosol by ER-associated degradation or ERAD pathway for...
5.0K
01:29Role of Reduced Coenzymes NADH and FADH₂
16.1K
The energy released from the breakdown of the chemical bonds within nutrients can be stored either through the reduction of electron carriers or in the bonds of adenosine triphosphate (ATP). In living systems, a small class of compounds functions as mobile electron carriers, molecules that bind to and shuttle high-energy electrons between compounds in pathways. The principal electron carriers that will be considered originate from the B vitamin group and are derivatives of nucleotides; they are...
16.1K
01:16Necrosis
6.2K
Necrosis is considered as an “accidental” or unexpected form of cell death that ends in cell lysis. The first noticeable mention of “necrosis” was in 1859 when Rudolf Virchow used this term to describe advanced tissue breakdown in his compilation titled “Cell Pathology”.
Morphological Manifestations of Necrosis
Necrotic cells show different types of morphological appearance depending on the type of tissue and infection. In coagulative necrosis, cells become...
Morphological Manifestations of Necrosis
Necrotic cells show different types of morphological appearance depending on the type of tissue and infection. In coagulative necrosis, cells become...
6.2K
01:37The Unfolded Protein Response
6.2K
The ER is the hub of protein synthesis in a cell. It has robust systems to quality control protein folding and also for degradation of terminally misfolded proteins. Under normal conditions, a small proportion of misfolded proteins that cannot be salvaged need to be transported to the cytoplasm by the ER-associated degradation or ERAD pathways. However, if the ERAD cannot handle the misfolded proteins, the cell activates the unfolded protein response or UPR to adjust the protein folding...
6.2K
01:31Regulation of the Unfolded Protein Response
2.9K
Inositol-requiring kinase one or IRE1 is the most conserved eukaryotic unfolded protein response (UPR) receptor. It is a type I transmembrane protein kinase receptor with a distinctive site-specific RNase activity. As the binding mechanics of the misfolded proteins with the N-terminal domain of IRE-1 are unclear, three binding models — direct, indirect, and allosteric -- are proposed for receptor activation. Nevertheless, it is known that once a misfolded protein associates with IRE1, it...
2.9K
00:50Anaphase Promoting Complex
3.3K
The stepwise destruction of specific proteins is necessary for the progression and completion of the cell cycle. Such proteins are ubiquitinated by ubiquitin ligases and then subsequently destroyed by the proteasome. The SCF (Skp1/Cullin/F-box) and the anaphase-promoting complex (APC) are two important ubiquitin ligases involved in cell cycle progression. While SCF is active throughout the cell cycle, APC gets activated during metaphase to anaphase transition. Cdc20 or Cdh1 binds to APC and...
3.3K