O-GlcNAc通过PINK1-依赖途径影响线粒
Ibtihal M Alghusen1, Marisa S Carman1, Heather M Wilkins1,2,3
1School of Medicine, Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, KS, United States.
Frontiers in aging neuroscience
|August 23, 2024
概括
功能失调的线粒体在阿尔茨海默病 (AD) 中积累. 这项研究表明,O-GlcNAc的修饰对于甲状腺化至关重要,甲状腺化的过程受损,突出了潜在的治疗标.
科学领域:
- 神经科学是一个神经科学.
- 细胞生物学 细胞生物学
- 生物化学 生物化学
背景情况:
- 线粒体功能障碍和受损线粒体的积累是阿尔茨海默病 (AD) 的早期特征.
- 在AD中受损的线粒体周转率导致活性氧物种增加,ATP减少,细胞毒性和神经退行.
- 阿尔茨海默病的特点是O-GlcNAc (β-N-乙糖胺) 修饰的破坏,这是细胞代谢和蛋白质功能的关键调节过程.
研究的目的:
- 调查O-GlcNAc修饰在调节线粒细胞衰变中的作用,受损线粒体的选择性自.
- 检查调节O-GlcNAc水平对AD细胞和动物模型中的线粒细胞衰变通路的影响.
主要方法:
- 利用患者衍生的诱导多能干细胞,转基因AD小鼠模型和SH-SY5Y神经母细胞瘤细胞系.
- 采用生物化学分析来评估线粒.
- 研究了O-GlcNAcase抑制 (Thiamet-G) 和OGT缺陷对线粒细胞衰变标记物的影响.
主要成果:
- O-GlcNAc在激活细胞化方面发挥着关键作用;刺激细胞化会降低细胞O-GlcNAc并增加线粒体O-GlcNAc.
- 通过 Thiamet-G (TMG) 抑制 O-GlcNAcase (OGA) 增加了线粒体中线粒体中线粒体蛋白 PINK1 和 LC3 的水平,在 PINK1.3 上有增加的 O-GlcNAc 的证据.
- 相反,通过OGT敲击降低O-GlcNAc水平,PINK1和LC3的表达减少,OGT缺乏小鼠的线粒体显示PINK1和LC3的减少.
结论:
- O-GlcNAc对于线粒的激活和进展至关重要.
- 在阿尔茨海默氏症中,O-GlcNAc介导的线粒的调节被破坏,这表明AD病原体的基础是一个新的机制.
相关概念视频
01:36Delivery Pathways to the Lysosome
6.2K
Eukaryotic cells use different mechanisms to eliminate toxic waste obsolete and worn-out substances. Lysosomes play a pivotal role in this, and hence, these substances are carried to the lysosome from other parts of the cell and extracellular space through different pathways. The most elaborately studied pathways to the lysosome are the endocytic pathways.
Endocytosis
In endocytosis, the cell membrane takes up macromolecules and particles from the surrounding medium. Clathrin-mediated...
Endocytosis
In endocytosis, the cell membrane takes up macromolecules and particles from the surrounding medium. Clathrin-mediated...
6.2K
01:19Translocation of Proteins into the Mitochondria
3.1K
Mitochondrial precursors are translocated to the internal subcompartments via independent mechanisms involving distinct protein machineries called translocases.
Sorting of outer membrane proteins:
Mitochondrial outer membrane proteins are of two types: the transmembrane, beta-barrel porins, and the membrane-anchored, alpha-helical proteins. Beta-barrel porin precursors are translocated by the TOM complex and inserted into the outer mitochondrial membrane by the SAM complex. In contrast,...
Sorting of outer membrane proteins:
Mitochondrial outer membrane proteins are of two types: the transmembrane, beta-barrel porins, and the membrane-anchored, alpha-helical proteins. Beta-barrel porin precursors are translocated by the TOM complex and inserted into the outer mitochondrial membrane by the SAM complex. In contrast,...
3.1K
01:32Export of Misfolded Proteins out of the ER
3.5K
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...
3.5K
01:27Autophagy
4.2K
Autophagy is a self-digesting process by which a cell protects itself from threats both within and outside the cell, ranging from abnormal proteins to invading bacteria. In this process, obsolete components of the cell and invading microbes are degraded by hydrolytic enzymes active in an acidic environment of the lysosomal lumen.
An autophagic pathway consists of a series of signaling events activated in response to diverse stress and physiological conditions such as food deprivation,...
An autophagic pathway consists of a series of signaling events activated in response to diverse stress and physiological conditions such as food deprivation,...
4.2K
01:46Electron Transport Chain: Complex I and II
12.4K
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...
12.4K