Oxoglutarate dehydrogenase complex controls glutamate-mediated neuronal death

Weidinger, Adelheid; Milivojev, Nadja; Hosmann, Arthur; Duvigneau, Johanna Catharina; Szabó, Csaba; Törő, Gábor; Rauter, Laurin; Vaglio-Garro, Annette; Mkrtchyan, Garik; Trofimova, L. K.; Sharipov, Rinat; Surin, Alexander; Krasilnikova, Irina; Pinelis, Vsevolod; Tretter, László; Moldzio, Rudolf; Bayır, Hülya; Kagan, Valerian E.; Bunik, Victoria I.; Kozlov, Andrey V.

doi:10.1016/j.redox.2023.102669

Cited by 19 publications

(18 citation statements)

References 47 publications

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“…Anxa2 is a Ca(2+)-dependent phospholipid-binding protein. Glutamate can induce intracellular Ca(2+) increase and lead to cell death [37]. Anxa2 is also an RNA-binding protein.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive analysis based on machine learning algorithm: Hspb1 and Lgals3 in neurons after spinal cord injury are closely related to autophagy

Yan

et al. 2023

Preprint

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Spinal cord injury (SCI) refers to the dysfunction of sensorimotor and autonomic nerves caused by extensive and permanent loss of neurons after different degrees of damage to the spinal cord or cauda equina. The mechanism of spinal cord neuron injury after SCI has not been fully elucidated so far, although some opinions have been put forward. In this study, we extracted primary spinal neurons from neonatal rats, constructed a neuron injury model using glutamate stimulation, and performed full transcriptome sequencing analysis. We used machine learning algorithm (WGCNA, RF, and LASSO) to comprehensively and in-depth explore the important genes of spinal cord neuron injury and screen out the key genes Anxa2, Ccng1, Hspb1, Lgals3, Timp1 and S100a10, which are accompanied by the up-regulation of six expression levels of spinal cord neuron injury. Importantly, Hspb1 and Lgals3 are closely related to autophagy. To improve the reliability of our results, we downloaded the corresponding expression levels of six key genes of GSE2599, GSE20907, GSE45006, and GSE174549 to make ROC curve for verification, and then conducted RT-PCR verification of six key genes in vitro and in vivo, respectively. These findings will help us to further understand the pathogenesis of SCI, and may contribute to the screening of key targets for future clinical treatment.

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“…Anxa2 is a Ca(2+)-dependent phospholipid-binding protein. Glutamate can induce intracellular Ca(2+) increase and lead to cell death [37]. Anxa2 is also an RNA-binding protein.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive analysis based on machine learning algorithm: Hspb1 and Lgals3 in neurons after spinal cord injury are closely related to autophagy

Yan

et al. 2023

Preprint

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“…Thiamine (vitamin B1), its natural derivative ThDP (cocarboxylase) and pharmacological forms (benfotiamin, sulbutiamin etc. [19]) are known to exhibit cardio-and neuroprotective actions under variety of conditions associated with dysfunctional mitochondria [1,[20][21][22]. Potential link between thiamine and the CMT disease symptoms is supported by an outbreak of a peripheral neuropathy similar to CMT disease in 88 male prisoners who exhibited hyporeflexia/areflexia of the lower extremities, sensory deficit and motor weakness.…”

Section: Vitamin B1-dependent Enzymesmentioning

confidence: 99%

Therapeutic Potential of Vitamins in Charcot-Marie-Tooth Disease with the Compromised Status of the Vitamin-Dependent Processes

Bunik¹

2023

Preprint

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Understanding molecular mechanisms of neurological disorders is required for development of personalized medicine. When the diagnosis considers not only the disease symptoms, but also their molecular basis, the treatments tailored for individual patients may be suggested. The vitamins-responsive neurological disorders are induced by deficiencies in the vitamin-dependent processes. The deficiencies may occur due to genetic impairments of proteins whose functions are involved with the vitamins. This review considers the enzymes encoded by DHTKD1, PDK3 and PDXK genes, whose mutations are observed in patients with Charcot-Marie-Tooth (CMT) disease. The enzymes bind or produce the coenzyme forms of vitamins B1 (thiamine diphosphate, ThDP) and B6 (pyridoxal-5’-phosphate, PLP). Alleviation of such disorders by administration of the lacking vitamin or its derivative calls upon a better introduction of the mechanistic knowledge to medical diagnostics and therapies. Recent data on lower levels of the vitamin B3 derivative, NAD+, in the blood of patients with CMT disease, compared to the control subjects, are also considered in view of the NAD-dependent mechanisms of pathological axonal degeneration, suggesting therapeutic potential of vitamin B3. Thus, improved diagnostics of the underlying causes of the CMT disease may allow the patients with the vitamin-responsive disease forms to benefit from the administration of the vitamins B1, B3, B6, their natural derivatives or pharmacological forms.

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“…Neuronal death upon neurodegenerative disorders and brain injury are associated with excessive production of NO and reactive oxygen species (ROS) [1], mitochondrial dysfunction [2,3] and glutamate toxicity [4,5]. Excessive production of ROS is associated with electron leak from the mitochondrial respiratory chain, while the excessive NO generation is linked to the activation of neuronal nitric oxide synthase (nNOS) [6].…”

Section: Introductionmentioning

confidence: 99%

“…Excessive production of ROS is associated with electron leak from the mitochondrial respiratory chain, while the excessive NO generation is linked to the activation of neuronal nitric oxide synthase (nNOS) [6]. The accumulation of extracellular glutamate is preceded by several upstream molecular events, for example, low oxoglutarate dehydrogenase complex (OGDHC) activity in mitochondria, activation of inducible nitric oxide synthase (iNOS), and spontaneous release of glutamate [7], which is controlled by mitochondria [3]. However, causal interaction between these three factors is still not completely understood.…”

Section: Introductionmentioning

confidence: 99%

“…Astrocytes collect excessiv glutamate that is released during synaptic transmission and convert it into non-toxic gl tamine by the glutamine synthetase [18][19][20][21][22]. Glutamine is subsequently transported in neurons to turn back into glutamate by the phosphate-activated glutaminase [18,20,23 Eventually, glutamate is packed in transmission vesicles or used in the mitochondrial t carboxylic acid (TCA) cycle to produce energy [3,7,24].…”

Section: Introductionmentioning

confidence: 99%

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Interplay between Energy Supply and Glutamate Toxicity in the Primary Cortical Culture

Vaglio-Garro,

Halasz,

Nováková

et al. 2024

Biomolecules

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Limited substrate availability because of the blood–brain barrier (BBB) has made the brain develop specific molecular mechanisms to survive, using lactate synthesized by astrocytes as a source of energy in neurons. To understand if lactate improves cellular viability and susceptibility to glutamate toxicity, primary cortical cells were incubated in glucose- or lactate-containing media and toxic concentrations of glutamate for 24 h. Cell death was determined by immunostaining and lactate dehydrogenase (LDH) release. Mitochondrial membrane potential and nitric oxide (NO) levels were measured using Tetramethylrhodamine, methyl ester (TMRM) and 4-Amino-5-Methylamino-2′,7′-Difluorofluorescein Diacetate (DAF-FM) live staining, respectively. LDH activity was quantified in single cells in the presence of lactate (LDH substrate) and oxamate (LDH inhibitor). Nuclei of cells were stained with DAPI and neurons with MAP2. Based on the distance between neurons and glial cells, they were classified as linked (<10 µm) and non-linked (>10 µm) neurons. Lactate increased cell death rate and the mean value of endogenous NO levels compared to glucose incubations. Mitochondrial membrane potential was lower in the cells cultured with lactate, but this effect was reversed when glutamate was added to the lactate medium. LDH activity was higher in linked neurons compared to non-linked neurons, supporting the hypothesis of the existence of the lactate shuttle between astrocytes and at least a portion of neurons. In conclusion, glucose or lactate can equally preserve primary cortical neurons, but those neurons having a low level of LDH activity and incubated with lactate cannot cover high energetic demand solely with lactate and become more susceptible to glutamate toxicity.

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Oxoglutarate dehydrogenase complex controls glutamate-mediated neuronal death

Cited by 19 publications

References 47 publications

Comprehensive analysis based on machine learning algorithm: Hspb1 and Lgals3 in neurons after spinal cord injury are closely related to autophagy

Comprehensive analysis based on machine learning algorithm: Hspb1 and Lgals3 in neurons after spinal cord injury are closely related to autophagy

Therapeutic Potential of Vitamins in Charcot-Marie-Tooth Disease with the Compromised Status of the Vitamin-Dependent Processes

Interplay between Energy Supply and Glutamate Toxicity in the Primary Cortical Culture

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