Beyond the redox imbalance: Oxidative stress contributes to an impaired GLUT3 modulation in Huntington's disease

Abstract

Failure in energy metabolism and oxidative damage are associated with Huntington’s disease (HD). Ascorbic acid released during synaptic activity inhibits use of neuronal glucose, favouring lactate uptake to sustain brain activity. Here, we observe a decreased expression of GLUT3 in STHdhQ111 cells (HD cells) and R6/2 mice (HD mice). Localisation of GLUT3 is decreased at the plasma membrane in HD cells affecting the modulation of glucose uptake by ascorbic acid. An ascorbic acid analogue without antioxidant activity is able to inhibit glucose uptake in HD cells. The impaired modulation of glucose uptake by ascorbic acid is directly related to ROS levels indicating that oxidative stress sequesters the ability of ascorbic acid to modulate glucose utilisation. Therefore, in HD, a decrease in GLUT3 localisation at the plasma membrane would contribute to an altered neuronal glucose uptake during resting periods while redox imbalance should contribute to metabolic failure during synaptic activity.

Oxidative Stress in Neurodegenerative Diseases: From Molecular Mechanisms to Clinical Applications

“…Initial studies support the theory that HD lowers energy levels, as reduced glucose usage and increased lactate levels are observed in HD patients [67, 73]. Recent research shows that oxidative damage is related to decreased expression of glucose transporter (GLUT)-3, resulting in inhibited glucose uptake and accumulation of lactate (Figure 1()) [73, 74]. The majority of ATP synthesis occurs through the generation of the proton motive force during operation of the electron transport chain [75].…”

Altered lactate metabolism in Huntington's disease is dependent on GLUT3 expression

“…We also observed an ascorbic acid‐stimulated increase in the proton concentration in Q7 cells without changes in Q111 cells (Figure B‐D). Ascorbic acid inhibits glucose uptake by a GLUT3‐dependent mechanism and HD neurons and Q111 cells exhibit a decrease in GLUT3 expression . Therefore, we reasoned that the failure in ascorbic acid‐dependent stimulation of lactate uptake could be a consequence of inhibited glucose transport.…”

“…Biotinylation assays were performed as previously was described by Covarrubias‐Pinto et al Surface proteins were labeled using Sulfo‐NHS‐LC‐Biotin (Thermo Fisher Scientific, Rockford, IL, USA). Labeled cells were homogenized in 200 μL of buffer RIPA (50 mmol/L Tris‐HCl, 150 mmol/L NaCl, 1% NP‐40, 12 mmol/L sodium deoxycholate, 1% SDS, 5 mmol/L EDTA, 0.3% Triton X‐100, pH 7.4) and protease inhibitors and then precipitated by continuous mixing with 40 μL of immobilized NeutrAvidin Protein (Thermo Fisher Scientific, Rockford, IL, USA) for 4 hours at 4°C.…”

“…Reduced TCA cycle activity and oxidative phosphorylation, decreased glyceraldehyde 3‐phosphate dehydrogenase activity, impaired oxidative phosphorylation enzyme activity and downregulation of peroxisome proliferator‐activated receptor‐γ have also been described. Decreased expression of the neuronal glucose transporter GLUT3 also occurs in HD …”

Assessment of carcinogenic potential of soft drinks of cola, diet cola, orange and lemon, produced in the city of Uberlândia, Minas Gerais state, Brazil

“…The presence of this ingredient may have acted as a counterbalance for oxidative stress, and acting in cell protection against oxygen reactive species (NUNES et al, 2015;BHUSAL et al, 2014;DU et al, 2014) and as preventive ingredient in diseases related to genetic instability (COVARRUBIAS-PINTO et al, 2015;TASHIMA et al, 2015;HIPOLITO et al, 2015;FINCK et al, 2014).…”