Pathological Interplay between Inflammation and Mitochondria Aggravates Glutamate Toxicity

Abstract

Mitochondrial dysfunction and glutamate toxicity are associated with neural disorders, including brain trauma. A review of the literature suggests that toxic and transmission actions of neuronal glutamate are spatially and functionally separated. The transmission pathway utilizes synaptic GluN2A receptors, rapidly released pool of glutamate, evoked release of glutamate mediated by Synaptotagmin 1 and the amount of extracellular glutamate regulated by astrocytes. The toxic pathway utilizes extrasynaptic GluN2B receptors and a cytoplasmic pool of glutamate, which results from the spontaneous release of glutamate mediated by Synaptotagmin 7 and the neuronal 2-oxoglutarate dehydrogenase complex (OGDHC), a tricarboxylic acid (TCA) cycle enzyme. Additionally, the inhibition of OGDHC observed upon neuro-inflammation is due to an excessive release of reactive oxygen/nitrogen species by immune cells. The loss of OGDHC inhibits uptake of glutamate by mitochondria, thus facilitating its extracellular accumulation and stimulating toxic glutamate pathway without affecting transmission. High levels of extracellular glutamate lead to dysregulation of intracellular redox homeostasis and cause ferroptosis, excitotoxicity, and mitochondrial dysfunction. The latter affects the transmission pathway demanding high-energy supply and leading to cell death. Mitochondria aggravate glutamate toxicity due to impairments in the TCA cycle and become a victim of glutamate toxicity, which disrupts oxidative phosphorylation. Thus, therapies targeting the TCA cycle in neurological disorders may be more efficient than attempting to preserve mitochondrial oxidative phosphorylation.

Keywords: TCA cycle; ferroptosis; glutamate; mitochondrial dysfunction; neuronal death.

Figure 1

Graphical abstract. The glutamateglutamate vicious toxic cycle (shown in red) occurs at the extrasynaptic site. Physiological glutamate-glutamine cycle (shown in green) is located in the synaptic cleft.

Figure 2

Distribution of glutamate in the nervous tissue, and the glutamate-glutamine cycle and its changes upon brain injury.

Figure 3

Evoked and spontaneous glutamate release, resulting in a balance between extracellular and intracellular glutamate pools. Spontaneous release and uptake of glutamate by GLT1 create a vicious Glutamate_in-Glutamate_out cycle.

Figure 4

The impact of mitochondria in mechanisms of glutamate-mediated neuronal death. When the oxoglutarate dehydrogenase enzyme is blocked in mitochondria, the glutamate accumulates. Inside the mitochondria, it can disrupt the normal function of the electron transport chain, where the remaining glutamate will leak into the cytoplasm and secreted into the extracellular fluid. The high concentration of glutamate in the extracellular fluid will affect other transporters like (1) the glutamate-cysteine antiporter, leading to the reduction of intracellular cysteine, and thus reducing the activity of enzymes of the family of the glutathione peroxidase, causing the accumulation of lipid peroxides that, together with iron, can cause ferroptosis. Additionally, (2) glutamate can cause excitotoxicity via activated extrasynaptically NMDA receptors.