Synaptic and Non-Synaptic Mitochondria in Hippocampus of Adult Rats Differ in Their Sensitivity to Hypothyroidism

Abstract

Hypothyroidism in humans provokes various neuropsychiatric disorders, movement, and cognitive abnormalities that may greatly depend on the mitochondrial energy metabolism. Brain cells contain at least two major populations of mitochondria that include the non-synaptic mitochondria, which originate from neuronal and glial cell bodies (CM), and the synaptic (SM) mitochondria, which primarily originate from the nerve terminals. Several parameters of oxidative stress and other parameters in SM and CM fractions of hippocampus of adult rats were compared among euthyroid (control), hypothyroid (methimazol-treated), and thyroxine (T4)-treated hypothyroid states. nNOS translocation to CM was observed with concomitant increase of mtNOS's activity in hypothyroid rats. In parallel, oxidation of cytochrome c oxidase and production of peroxides with substrates of complex I (glutamate + malate) were enhanced in CM, whereas the activity of aconitase and mitochondrial membrane potential (ΔΨm) were decreased. Furthermore, the elevation of mitochondrial hexokinase activity in CM was also found. No differences in these parameters between control and hypothyroid animals were observed in SM. However, in contrast to CM, hypothyroidism increases the level of pro-apoptotic K-Ras and Bad in SM. Our results suggest that hypothyroidism induces moderate and reversible oxidative/nitrosative stress in hippocampal CM, leading to the compensatory elevation of hexokinase activity and aerobic glycolysis. Such adaptive activation in glycolytic metabolism does not occur in SM, suggesting that synaptic mitochondria differ in their sensitivity to the energetic disturbance in hypothyroid conditions.

Hormonal Regulation of Oxidative Phosphorylation in the Brain in Health and Disease

“…Moreover, the observed effects were correlated with decreased free mitochondrial biogenesis in the CM of the cerebral cortex, and it is hypothesized that the impact of THs on free mitochondrial biogenesis could underlie their effects on respiration [ 85 ]. Interestingly, mitochondrial respiration changes in the abovementioned studies [ 83 , 84 , 85 ] were observed in CM but not in the synaptosomal mitochondrial fraction. Moreover, in CM mitochondria, the aerobic glycolysis process (measured as formation of lactate) was increased, which was connected with hexokinase—initial, rate-limiting enzyme of glycolysis located on the mitochondria outer membrane—activity enhancement.…”

“…Currently, research increasingly differentiates the function of mitochondria depending on their location in nervous tissue and distinguishes two major populations of mitochondria: those derived from neuronal and glial cell bodies (CM) and synaptic mitochondria (SM) versus those derived from nerve terminals. Zhuravliova et al [ 83 ] demonstrated elevated redox level of copper of cytochrome oxidase and increased production of peroxides in the presence of substrates of complex I (glutamate and malate) in the CM of hippocampi of hypothyroid (methimazole-treated) rats, whereas succinate-induced H 2 O 2 release was diminished. Furthermore, previous data [ 84 , 85 ] showed that in the CM of hypothyroid neonates, there was diminished activity of complex I and reduced transmembrane potential, rate of oxidative phosphorylation and oxygen consumption.…”

“…Moreover, in CM mitochondria, the aerobic glycolysis process (measured as formation of lactate) was increased, which was connected with hexokinase—initial, rate-limiting enzyme of glycolysis located on the mitochondria outer membrane—activity enhancement. Adaptive activation in glycolytic metabolism was not observed in SM, which shows that synaptic mitochondria differ in their sensitivity to energetic dysregulation in hypothyroidism [ 83 ]. Much less research concerns metabolic changes in the brain through the course of hyperthyroidism.…”

Molecular mechanisms of neuroprotective effects of thyroid hormones and their metabolites in acute brain ischemia

“…Полученные данные позволяют чётко дифференцировать две фракции митохондрий: в телах нейрональных, глиальных клеток и в синапсах. По данным E. Zhuravliova и соавт., при гипотиреозе в митохондриях нейронов и глии усиливался аэробный гликолиз, связанный с активностью гексокиназы, при этом адаптивная активация распада глюкозы в синаптических митохондриях не наблюдалась [32]. Т3 может противодействовать неблагоприятным изменениям, наблюдаемым в митохондриях нейронов головного мозга при гипотиреозе, путём нормализации дыхательных процессов и регуляции транскрипции митохондриальных генов (ND4, 12S рРНК, 16S рРНК и Cox III) [33].…”

Brain Mitochondrial Dysfunction: A Possible Mechanism Links Early Life Anxiety to Alzheimer’s Disease in Later Life

“…There are roughly two sources of mitochondria in the brain. One is called non-synaptic mitochondria, mainly from neurons and glial cell bodies, and the other is called synaptic mitochondria, mainly from nerve terminals [ 35 ]. Using two-dimensional differential gel electrophoresis and mass spectrometry to detect synaptic proteins, the data show significant differences in superoxide dismutase [Mn] (Sod2) and complement component 1Q subcomponent binding protein (C1qbp), which supports the idea that synapses are highly sensitive to oxidative stress[ 36 ].…”