Inflammation and Redox Homeostasis Induces Type 3 Deiodinase and Impacts Brain Endoplasmic Reticulum–Mitochondria Crosstalk Both in Local and Systemic Disease Models

Abstract

Abstract Thyroid hormone is the leading regulator of cell energy production in most tissues, mainly the brain. While the activation process of T4 into T3 depends on D1 and D2 deiodinases, type 3 is the main enzyme that inactivates T3. Several mechanisms, among them oxidative stress, led by disease, imbalances and induces D3, diminishing T3 levels. The response of D3 in the brain in the context of different disease models has yet to be studied. Here we evaluated D3 induction in the brain in two animal disease models, one systemic and the other local. Methodology: To the metabolic dysfunction-associated steatotic liver disease model Male/adult Sprague Dawley rats (n = 20) were assigned to control group (standard diet–2.93kcal/g) or high-fat-diet group (CDHF–4.3kcal/g). In the streptozotocin-induced (STZ) Alzheimer's model Adult Wistar rats (n = 16) were allocated to the control group (5uL of citrate) or 5uL of streptozotocin. Sham animals were used as controls. D3 expression, oxidative stress parameters, endoplasmic stress and mitochondrial amount measured in the brain. Levels of D3 increased in the brain (~ 30% in each group, P < 0.0001) in both MASLD and STZ groups. Cerebral tissue from both groups had augmented carbonyl levels (P < 0.001) and reduced sulfhydryl (P < 0.001). Glutathione was diminished. Antioxidant defenses were altered with endoplasmic reticulum stress and altered mitochondrial concentration (P = 0.001). The augmented T3 inactivation by D3 dysfunction in brain due to oxidative stress disrupts ER-mitochondrial contact interaction, changing the function of both organelles in the brain.