协酶A通过对氨酸减少酶2的CoAlation来保护铁
Jen-Tsan Chi1, Chao Chieh Lin1, Yi-Tzu Lin1
1Duke University.
Research square
|July 1, 2024
概括
辅酶A (CoA) 通过调节线粒体的硫素系统来保护铁亡. 补充CoA可以防止xCT抑制剂诱导的铁亡,从而揭示了一个新的保护性途径.
科学领域:
- 生物化学 生物化学
- 细胞生物学 细胞生物学
- 分子医学是分子医学.
背景情况:
- 囊-xCT 载体-氨酸 (GSH) -GPX4轴对铁亡保护至关重要.
- 化诱导化合物 (FINs) 向xCT转运器需要线粒体,与向GPX4的化合物不同,但机制尚不清楚.
研究的目的:
- 调查针对xCT和GPX4.4的FIN的差异效应背后的机制.
- 探索协酶A (CoA) 在铁灭调节中的作用.
主要方法:
- 补充CoA以评估其对xCT和GPX4抑制剂诱导的铁死的影响.
- 使用奥拉诺芬 (铁素减少酶抑制剂) 来探测CoA的保护机制.
- 调查CoA可用性对铁素还原酶和铁素活性的影响.
- 分析 mitochondrial thioredoxin 系统在 CoA 介导的铁灭抑制中的作用.
- 通过CoA (CoAlation) 检查线粒体 thioredoxin 减少酶 (TXNRD2) 的共价修饰.
- 针对TXNRD2 (Cys-483转化为氨酸) 的局部定向突变发生,以评估其功能意义.
- 评估患者衍生纤维细胞中的铁灭症,并破坏了CoA代谢.
- 评估CoA生物合成抑制在器官类型脑切片培养中的影响.
主要成果:
- CoA 补充剂专门防止了由xCT 抑制剂引起的铁亡,而不是GPX4 抑制剂.
- 奥拉诺芬取消了CoA的保护作用,表明了硫素系统的作用.
- CoA的可用性调节了 thioredoxin减少酶的活性,特别是线粒体TXNRD2.
- 在Cys-483 (CoAlation) 位点共修饰的CoATXNRD2,对其酶活性和铁灭保护至关重要.
- 向xCT降低了TXNRD2协同反应,由CoA补充剂来挽救.
- 干扰CoA新陈代谢的纤维细胞显示线粒体脂质过氧化增加.
- 在大脑切片中抑制CoA生物合成导致铁亡,由铁素-1.1挽救.
结论:
- 辅酶A通过TXNRD2的翻译后修饰 (CoAlation) 调节线粒体的硫素系统,这代表了一个替代的铁灭保护途径.
- 这种由CoA介导的途径对于防止铁亡至关重要,特别是在CoA代谢中断的情况下.
- 这些发现突显了CoA代谢在ferroptosis中的临床相关性,并提出了潜在的治疗策略.
更多相关视频
08:04Cone-Enriched Cultures from the Retina of Chicken Embryos to Study Rod to Cone Cellular Interactions
Published on: March 20, 2021
3.6K
04:48Setup of Capillary Electrophoresis-Inductively Coupled Plasma Mass Spectrometry CE-ICP-MS for Quantification of Iron Redox Species FeII, FeIII
Published on: May 4, 2020
8.0K
相关概念视频
Role of Reduced Coenzymes NADH and FADH₂
11.3K
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...
11.3K
Electron Transport Chain: Complex I and II
12.8K
The mitochondrial electron transport chain (ETC) is the main energy generation system in the eukaryotic cells. However, mitochondria also produce cytotoxic reactive oxygen species (ROS) due to the large electron flow during oxidative phosphorylation. While Complex I is one of the primary sources of superoxide radicals, ROS production by Complex II is uncommon and may only be observed in cancer cells with mutated complexes.
ROS generation is regulated and maintained at moderate levels necessary...
ROS generation is regulated and maintained at moderate levels necessary...
12.8K
Electron Transport Chain: Complex III and IV
7.3K
During the electron transport chain, electrons from NADH and FADH2 are first transferred to complexes I and II, respectively. These two complexes then transfer the electrons to ubiquinol, which carries them further to complex III. Complex III passes the electrons across the intermembrane space to Cyt c, which carries them further to complex IV. Complex IV donates electrons to oxygen and reduces it to water. As electrons pass through complexes I, III, and IV, the energy released aids the pumping...
7.3K
The Electron Transport Chain
16.5K
The electron transport chain or oxidative phosphorylation is an exothermic process in which free energy released during electron transfer reactions is coupled to ATP synthesis. This process is a significant source of energy in aerobic cells, and therefore inhibitors of the electron transport chain can be detrimental to the cell's metabolic processes.
Inhibitors of the electron transport chain
Rotenone, a widely used pesticide, prevents electron transfer from Fe-S cluster to ubiquinone or Q...
Inhibitors of the electron transport chain
Rotenone, a widely used pesticide, prevents electron transfer from Fe-S cluster to ubiquinone or Q...
16.5K
Oxidation of Phenols to Quinones
3.0K
In the presence of oxidizing agents, phenols are oxidized to quinones. Quinones can be easily reduced back to phenols using mild reducing agents. The electron-donating hydroxyl group enhances the reactivity of the aromatic ring, enabling oxidation of the ring even in the absence of an α hydrogen.
o-hydroxy phenols are oxidized to o-quinones and p-hydroxy phenols to p-quinones. Such redox reactions involve the transfer of two electrons and two protons. The reversible redox...
o-hydroxy phenols are oxidized to o-quinones and p-hydroxy phenols to p-quinones. Such redox reactions involve the transfer of two electrons and two protons. The reversible redox...
3.0K
Cofactors and Coenzymes
11.0K
Enzymes are proteins made of amino acids. The functional group of each constituent amino acid catalyzes a wide variety of chemical reactions via ionic interactions or acid-base reactions. However, amino acids cannot catalyze oxidation-reduction and group transfer reactions and need to be aided by non-protein components called cofactors. Cofactors are also referred to as the chemical teeth of an enzyme.
Cofactors can be metallic ions or organic molecules called coenzymes. These types of helper...
Cofactors can be metallic ions or organic molecules called coenzymes. These types of helper...
11.0K
