Succinate causes oxidative damage through N-methyl-d-aspartate-mediated mechanisms

Sinhorin, Valéria Dornelles Gindri; Roehrs, C.; Pasin, Juliana Saibt Martins; Bellé, N.A.V.; Rubin, Maribel Antonello; Mello, Carlos Fernando

doi:10.1016/j.brainres.2005.05.053

Cited by 7 publications

(6 citation statements)

References 41 publications

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“…In hyperglycaemic conditions, excess ROS produced by the inflammatory and oxidative stress microenvironment in the bone marrow may induce cell damage and the apoptosis of stem/progenitor cells and alter the bone marrow niche, resulting in impaired bone metabolism in diabetic patients41. The activities of oxidative enzymes in mitochondria—including SDH, malate dehydrogenase, glutamate dehydrogenase, and isocitrate dehydrogenase—are closely related to ROS production42434445. The accumulation of succinate, malate, glutamate and citrate that is observed in T2D BMSCs (Supplementary Table 1) indicates that hyperglycaemia impairs the activities of these enzymes in bone.…”

Section: Discussionmentioning

confidence: 99%

Succinate and its G-protein-coupled receptor stimulates osteoclastogenesis

Guo

Xie

et al. 2017

Nat Commun

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The mechanism underlying bone impairment in patients with diabetes mellitus, a metabolic disorder characterized by chronic hyperglycaemia and dysregulation in metabolism, is unclear. Here we show the difference in the metabolomics of bone marrow stromal cells (BMSCs) derived from hyperglycaemic (type 2 diabetes mellitus, T2D) and normoglycaemic mice. One hundred and forty-two metabolites are substantially regulated in BMSCs from T2D mice, with the tricarboxylic acid (TCA) cycle being one of the primary metabolic pathways impaired by hyperglycaemia. Importantly, succinate, an intermediate metabolite in the TCA cycle, is increased by 24-fold in BMSCs from T2D mice. Succinate functions as an extracellular ligand through binding to its specific receptor on osteoclastic lineage cells and stimulates osteoclastogenesis in vitro and in vivo. Strategies targeting the receptor activation inhibit osteoclastogenesis. This study reveals a metabolite-mediated mechanism of osteoclastogenesis modulation that contributes to bone dysregulation in metabolic disorders.

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Section: Discussionmentioning

confidence: 99%

Succinate and its G-protein-coupled receptor stimulates osteoclastogenesis

Guo

Xie

et al. 2017

Nat Commun

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“…There is a close correspondence between succinate accumulation and ROS production [ 19 , 21 ]. Physiologically, succinate is metabolized via the fumarate-malate-oxaloacetate pathway by SDH to maintain mitochondrial homeostasis [ 59 , 60 ].…”

Section: Discussionmentioning

confidence: 99%

“…NMDA receptor activation also contributes to succinate accumulation [ 21 ]. Neonatal hypoxia promotes glutamate release and NMDA receptor activation [ 10 , 12 ].…”

Section: Discussionmentioning

confidence: 99%

“…Succinate treatment causes convulsions in mice [ 20 ]. NMDA receptors are involved in oxidative damage caused by succinate accumulation [ 21 ]. MK-801 (an NMDA receptor antagonist) attenuates convulsions and oxidative damage caused by succinate accumulation [ 21 ].…”

Section: Introductionmentioning

confidence: 99%

“…NMDA receptors are involved in oxidative damage caused by succinate accumulation [ 21 ]. MK-801 (an NMDA receptor antagonist) attenuates convulsions and oxidative damage caused by succinate accumulation [ 21 ]. Hypoxia causes glutamate release and NMDA receptor activation [ 22 ].…”

Section: Introductionmentioning

confidence: 99%

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Attenuated succinate accumulation relieves neuronal injury induced by hypoxia in neonatal mice

et al. 2022

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Hypoxia causes neonatal neuronal damage. However, the underlying mechanism remains unclear. This study aimed to explore the changes in succinate levels and identify the mechanisms underlying their contribution to hypoxia-induced damage in newborn mice. The neonatal C57BL/6J mouse hypoxia model was used in our study. We evaluated the levels of succinate, iron, reactive oxygen species (ROS), and mitochondrial ROS, and assessed mitophagy, neuronal damage, and learning and memory function, after hypoxia treatment. The neonatal mice showed increased succinate levels in the early hypoxia stage, followed by increased levels of oxidative stress, iron stress, neuronal damage, and cognitive deficits. Succinate levels were significantly reduced following treatment with inhibitors of succinate dehydrogenase (SDH), purine nucleotide cycle (PNC), and malate/aspartate shuttle (MAS), with the corresponding attenuation of oxidative stress, iron stress, neuronal damage, and cognitive impairment. Reversal catalysis of SDH through fumarate from the PNC and MAS pathways might be involved in hypoxia-induced succinate accumulation. Succinate accumulation in the early period after hypoxia may crucially contribute to oxidative and iron stress. Relieving succinate accumulation at the early hypoxia stage could prevent neuronal damage and cognitive impairment in neonatal hypoxia.

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1H NMR-based metabonomic analysis of brain in rats of morphine dependence and withdrawal intervention

Deng

et al. 2012

Behavioural Brain Research

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Succinate causes oxidative damage through N-methyl-d-aspartate-mediated mechanisms

Cited by 7 publications

References 41 publications

Succinate and its G-protein-coupled receptor stimulates osteoclastogenesis

Succinate and its G-protein-coupled receptor stimulates osteoclastogenesis

Attenuated succinate accumulation relieves neuronal injury induced by hypoxia in neonatal mice

1H NMR-based metabonomic analysis of brain in rats of morphine dependence and withdrawal intervention

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