Krebs Cycle Intermediates Protective against Oxidative Stress by Modulating the Level of Reactive Oxygen Species in Neuronal HT22 Cells

Abstract

Krebs cycle intermediates (KCIs) are reported to function as energy substrates in mitochondria and to exert antioxidants effects on the brain. The present study was designed to identify which KCIs are effective neuroprotective compounds against oxidative stress in neuronal cells. Here we found that pyruvate, oxaloacetate, and α-ketoglutarate, but not lactate, citrate, iso-citrate, succinate, fumarate, or malate, protected HT22 cells against hydrogen peroxide-mediated toxicity. These three intermediates reduced the production of hydrogen peroxide-activated reactive oxygen species, measured in terms of 2′,7′-dichlorofluorescein diacetate fluorescence. In contrast, none of the KCIs—used at 1 mM—protected against cell death induced by high concentrations of glutamate—another type of oxidative stress-induced neuronal cell death. Because these protective KCIs did not have any toxic effects (at least up to 10 mM), they have potential use for therapeutic intervention against chronic neurodegenerative diseases.

Targeting mitochondria with folic acid and vitamin B12ameliorates nicotine mediated islet cell dysfunction

“…Krebs cycle intermediates are protective against oxidative stress by modulating the level of ROS and they functions as energy donors and precursors for the synthesis of amino acids, lipids, and carbohydrates . The α‐KGDH, being an important regulatory site in the mitochondrial metabolism, when inhibited restricts the amount of NADH usable for the respiratory chain and mean while raised accumulation of NADPH makes an addition to the H 2 O 2 ‐induced declined in the amount of reduced pyridine nucleotides.…”

Drosophila SLC22 Orthologs Related to OATs, OCTs, and OCTNs Regulate Development and Responsiveness to Oxidative Stress

“…However, it is specifically expressed in the Malpighian tubules, which are often considered somewhat analogous to the mammalian kidneys, where excretion of the antioxidant-acting oxoacids of the TCA cycle, uric acid, and flavonoids normally occurs via OATs [15,[62][63][64]. TCA intermediates pyruvate, oxaloacetate, and α-ketoglutarate are known to mediate oxidative stress responses, due to direct interaction of their α-ketoacid structure with reactive oxygen species such as H 2 O 2 [48,65,66]. Due to the conservation of metabolites between Drosophila and humans, we raise the possibility that RNAi knockdowns of potential OAT orthologs would be more resistant to PQ due to increased systemic levels of metabolites with antioxidant properties.…”

Carbohydrate, glutathione, and polyamine metabolism are central to Aspergillus flavus oxidative stress responses over time

“…NRRL3357 displayed increased demand for TCA intermediates showing significant decreases in most quantified metabolites in the cycle while AF13 showed no significant differences (Figure 3). These compounds have been shown to provide some antioxidant benefit when supplemented to cultured neuronal cells (Sawa et al 2017), though a more likely explanation is the use of these compounds in the synthesis of amino acids and/or their derivatives involved in oxidative stress remediation. Increases in glucose and fructose under stress in both isolates may also be reflective of higher levels of metabolic demand for simple sugars, and the beginnings of carbon starvation leading to gluconeogenesis (Dijkema et al 1985; Lima et al 2014), particularly at 7 DAI (Figure 3).…”