Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Laboratory of Bioenergetics and Mitochondrial Phisiology, Av. Carlos Chagas Filho 373, Centro de Ciências da Saúde (CCS), Cidade Universitária, Rio de Janeiro, RJ, CEP: 21941902, Brazil.
Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Laboratory of Bioenergetics and Mitochondrial Phisiology, Av. Carlos Chagas Filho 373, Centro de Ciências da Saúde (CCS), Cidade Universitária, Rio de Janeiro, RJ, CEP: 21941902, Brazil.
Free Radic Biol Med. 2020 Nov 20;160:796-806. doi: 10.1016/j.freeradbiomed.2020.09.017. Epub 2020 Sep 17.
Hyperglycemia associated with Diabetes Mellitus type 1 (DM1) comorbidity may cause severe complications in several tissues that lead to premature death. These dysfunctions are related, among others, to redox imbalances caused by the uncontrolled cellular levels of reactive oxygen species (ROS). Brain is potentially prone to develop diabetes complications because of its great susceptibility to oxidative stress. In addition to antioxidant enzymes, mitochondria-coupled hexokinase (mt-HK) plays an essential role in maintaining high flux of oxygen and glucose to control the mitochondrial membrane and redox potential in brain. This redox control is critical for healthy conditions in brain and in the pathophysiological progression of DM1. The mitochondrial and mt-HK contribution in this process is essential to understand the relationship between DM1 complications and the management of the cellular redox balance. Using a rat model of one month of hyperglycemia induced by a single administration intraperitoneally of streptozotocin, we showed in the present work that, in rat brain mitochondria, there is a specifically reduction of the mitochondrial complex I (CI) activity and an increase in the activity of the antioxidant enzyme thioredoxin reductase, which are related to decreased hydrogen peroxide generation, oxygen consumption and mt-HK coupled-to-OxPhos activity via mitochondrial CI. Surprisingly, DM1 increases respiratory parameters and mt-HK activity via mitochondrial complex II (CII). This way, for the first time, we provide evidence that early progression of hyperglycemia, in brain tissue, changes the coupling of glucose phosphorylation at the level of mitochondria by rearranging the oxidative machinery of brain mitochondria towards CII dependent electron harvest. In addition, DM1 increased the production of HO by α-ketoglutarate dehydrogenase without causing oxidative stress. Finally, DM1 increased the oxidation status of PTEN and decreased the activation of NF-kB in DM1. These results indicate that this reorganization of glucose-oxygen-ROS axis in mitochondria may impact turnover of glucose, brain amino acids, redox and inflammatory signaling. In addition, this reorganization may be involved in early protection mechanisms against the development of cognitive degeneration and neurodegenerative disease, widely associated to mitochondrial CI deficits.
1 型糖尿病（DM1）合并症引起的高血糖可能导致多个组织发生严重并发症，从而导致过早死亡。这些功能障碍与活性氧（ROS）细胞水平失控引起的氧化还原失衡有关。由于大脑对氧化应激的高度敏感性，因此大脑容易发生糖尿病并发症。除了抗氧化酶外，线粒体偶联己糖激酶（mt-HK）在维持高氧气和葡萄糖通量以控制大脑线粒体膜和氧化还原电势方面发挥着至关重要的作用。这种氧化还原控制对于大脑的健康状况以及 DM1 的病理生理进展至关重要。线粒体和 mt-HK 在这一过程中的贡献对于理解 DM1 并发症与细胞氧化还原平衡的管理之间的关系至关重要。使用腹腔内单次注射链脲佐菌素诱导一个月高血糖的大鼠模型，我们在本研究中表明，在大鼠脑线粒体中，线粒体复合物 I（CI）的活性特异性降低，抗氧化酶硫氧还蛋白还原酶的活性增加，这与通过线粒体 CI 产生的过氧化氢生成、耗氧量和 mt-HK 偶联-OxPhos 活性降低有关。令人惊讶的是，DM1 通过线粒体复合物 II（CII）增加呼吸参数和 mt-HK 活性。通过这种方式，我们首次提供了证据，表明高血糖的早期进展改变了脑组织中线粒体中葡萄糖磷酸化的偶联，通过重新排列脑线粒体的氧化机制，使其朝向 CII 依赖的电子捕获。此外，DM1 增加了 α-酮戊二酸脱氢酶产生的 HO，而不会引起氧化应激。最后，DM1 增加了 PTEN 的氧化状态并降低了 NF-kB 在 DM1 中的激活。这些结果表明，线粒体中葡萄糖-氧气-ROS 轴的这种重排可能会影响葡萄糖、脑氨基酸、氧化还原和炎症信号的周转。此外，这种重排可能与广泛与线粒体 CI 缺陷相关的认知退化和神经退行性疾病的早期保护机制有关。
