当前位置: X-MOL 学术Mol. Cell. Neurosci. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Depressed mitochondrial function and electron transport Complex II-mediated H2O2 production in the cortex of type 1 diabetic rodents
Molecular and Cellular Neuroscience ( IF 3.5 ) Pub Date : 2018-05-23 , DOI: 10.1016/j.mcn.2018.05.006
Subir Roy Chowdhury , Jelena Djordjevic , Ella Thomson , Darrell R. Smith , Benedict C. Albensi , Paul Fernyhough

Aims

Abnormalities in mitochondrial function under diabetic conditions can lead to deficits in function of cortical neurons and their support cells exhibiting a pivotal role in the pathogenesis of several neurodegenerative disorders, including Alzheimer's disease. We aimed to assess mitochondrial respiration rates and membrane potential or H2O2 generation simultaneously and expression of proteins involved in mitochondrial dynamics, ROS scavenging and AMPK/SIRT/PGC-1α pathway activity in cortex under diabetic conditions.

Methods

Cortical mitochondria from streptozotocin (STZ)-induced type 1 diabetic rats or mice, and aged-matched controls were used for simultaneous measurements of mitochondrial respiration rates and mitochondrial membrane potential (mtMP) or H2O2 using OROBOROS oxygraph. Measurements of enzymatic activities of respiratory complexes were performed using spectophotometry. Protein levels in cortical mitochondria and homogenates were determined by Western blotting.

Results

Mitochondrial coupled respiration rates and FCCP-induced uncoupled respiration rates were significantly decreased in mitochondria of cortex of STZ-diabetic rats compared to controls. The mtMP in the presence of ADP was significantly depolarized and succinate-dependent respiration rates and H2O2 were significantly diminished in cortical mitochondria of diabetic animals compared to controls, accompanied with reduced expression of CuZn- and Mn-superoxide dismutase. The enzymatic activities of Complex I, II, and IV and protein levels of certain components of Complex I and II, mitofusin 2 (Mfn2), dynamin-related protein 1 (DRP1), P-AMPK, SIRT2 and PGC-1α were significantly diminished in diabetic cortex.

Conclusion

Deficits in mitochondrial function, dynamics, and antioxidant capabilities putatively mediated through sub-optimal AMPK/SIRT/PGC-1α signaling, are involved in the development of early sub-clinical neurodegeneration in the cortex under diabetic conditions.



中文翻译:

1型糖尿病啮齿动物皮层的线粒体功能降低和电子传递复合体II介导的H 2 O 2产生

目的

糖尿病条件下线粒体功能异常可导致皮质神经元功能缺失,其支持细胞在包括阿尔茨海默氏病在内的多种神经退行性疾病的发病机理中发挥关键作用。我们旨在同时评估糖尿病条件下皮质中线粒体呼吸速率和膜电位或H 2 O 2的产生,以及参与线粒体动力学,ROS清除和AMPK / SIRT /PGC-1α途径活性的蛋白质的表达。

方法

来自链脲佐菌素(STZ)诱导的1型糖尿病大鼠或小鼠的皮质线粒体以及年龄匹配的对照使用OROBOROS oxygraph同时测量线粒体呼吸速率和线粒体膜电位(mtMP)或H 2 O 2。使用分光光度法测量呼吸复合物的酶活性。通过蛋白质印迹法测定皮质线粒体和匀浆中的蛋白质水平。

结果

与对照组相比,STZ-糖尿病大鼠皮质的线粒体线粒体耦合呼吸速率和FCCP诱导的非耦合呼吸速率显着降低。与对照组相比,糖尿病动物的皮质线粒体中存在ADP的mtMP显着去极化,琥珀酸依赖性呼吸速率和H 2 O 2显着降低,同时CuZn和Mn超氧化物歧化酶表达降低。复合物I,II和IV的酶活性以及复合物I和II,线粒体蛋白2(Mfn2),动力蛋白相关蛋白1(DRP1),P-AMPK,SIRT2和PGC-1α某些组分的蛋白质水平显着降低在糖尿病皮层中。

结论

通过亚最佳的AMPK / SIRT /PGC-1α信号传导介导的线粒体功能,动力学和抗氧化能力的缺陷,参与了糖尿病条件下皮质早期亚临床神经退行性疾病的发展。

更新日期:2018-05-23
down
wechat
bug