协酶A通过对线粒体硫素减少酶的CoAlation来保护铁
Chao-Chieh Lin1, Yi-Tzu Lin1, Ssu-Yu Chen1
1Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, United States of America.
The Journal of clinical investigation
|July 22, 2025
概括
辅酶A (CoA) 补充剂通过调节线粒体的硫素系统来预防铁亡. CoA修改了线粒体硫素还原酶 (TXNRD2),提供了一个新的铁灭菌保护途径.
科学领域:
- 细胞生物学 细胞生物学
- 生物化学 生物化学
- 代谢途径 代谢途径
背景情况:
- 囊-xCT输送物-氨酸 (GSH) -GPX4轴对细胞对铁亡的保护至关重要.
- 虽然GPX4向铁致死诱导化合物 (FIN) 是线粒体独立的,但xCT向FIN则需要通过不清楚的机制进行线粒体脂质过氧化.
研究的目的:
- 研究辅酶A (CoA) 在铁灭中的作用,特别是与xCT抑制和线粒体功能的关系.
- 阐明CoA影响铁亡的机制,并确定潜在的治疗点.
主要方法:
- 补充CoA以观察其对xCT抑制诱导的铁亡的作用.
- 在体外的酶定量测试以评估CoA对线粒体氨酸减少酶 (TXNRD2) 活性的调节.
- 针对TXNRD2 (Cys-483到氨酸) 的位点定向突变发生,以确定CoA介导的修饰的作用.
- 分析患者衍生纤维细胞与破坏的CoA代谢和器官类型的脑切片培养.
主要成果:
- 补充CoA可以选择性地预防由xCT抑制引发的铁亡.
- CoA通过一种称为"CoAlation"的翻译后修饰在Cys-483.3直接调节TXNRD2酶活性.
- 在TXNRD2中Cys-483的突变取消了它的活性和对铁灭的保护功能.
- 由于xCT向减少了TXNRD2 CoAlation,导致线粒体脂质过氧化增加.
- 干扰CoA代谢的纤维细胞和抑制CoA生物合成的脑切片显示了线粒体脂质过氧化和细胞死亡的增加,这些被ferrostatin-1.1拯救了.
结论:
- 通过CoA介导的硫素系统的翻译后修改代表了铁灭保护的替代途径.
- 这条通路对囊的可用性和CoA生物合成敏感.
- 这些发现突出了对管理受损CoA代谢的患者的铁亡的潜在临床相关性.
相关概念视频
Electron Transport Chain: Complex I and II
15.0K
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...
15.0K
The Electron Transport Chain
17.3K
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...
17.3K
Electron Transport Chain: Complex III and IV
8.1K
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...
8.1K
Role of Reduced Coenzymes NADH and FADH₂
12.5K
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...
12.5K
The Supercomplexes in the Crista Membrane
2.6K
The mitochondrial cristae membrane is the primary site for the oxidative phosphorylation (OXPHOS) process of energy conversion mediated through respiratory complexes I to V. These complexes have been widely studied for decades, and it has been proven that they form supramolecular structures called respiratory supercomplexes (SC). These higher-order complexes may be crucial in maintaining the biochemical structure and improving the physiological activity of the individual complexes while...
2.6K
Sulfur Assimilation
77
Sulfur is an essential element in biological systems, contributing to synthesizing key biomolecules, including amino acids such as cysteine and methionine, and cofactors such as coenzyme A and biotin. Microorganisms primarily assimilate sulfur as sulfate (SO₄²⁻) from the environment, which must undergo a series of biochemical transformations before it can be incorporated into cellular components. As sulfate is highly oxidized, it must undergo assimilatory sulfate reduction to...
77


