Hyperglycemia in a type 1 Diabetes Mellitus model causes a shift in mitochondria coupled-glucose phosphorylation and redox metabolism in rat brain

• Published in: Free radical biology & medicine 2020-11, Vol.160, p.796-806
• Main Authors: Silva-Rodrigues, Thaia, de-Souza-Ferreira, Eduardo, Machado, Caio Mota, Cabral-Braga, Bruno, Rodrigues-Ferreira, Clara, Galina, Antonio
• Format: Article
• Language: English
• Subjects: Diabetes mellitus type 1; Mitochondrial brain metabolism; Mitochondrial hexokinase; Mitochondrial ROS; NF-kB; PTEN; Redox signaling
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2020.09.017

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 H2O2 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. [Display omitted] •DM1 causes a metabolic shift in the brain mitochondria from CI to CII..•The activity of