Abstract Neurodegenerative diseases are major global health problems with increasing incidence rates. A large amount of data suggests that excitotoxicity is a potential target of neurodegenerative diseases. However, effective pharmacological interventions against excitotoxicity are lacking. We aimed to elucidate the neuroprotective effect and mechanism of the mitochondrion-targeted NOX inhibitor mito-apocynin on kainic acid (KA)-induced excitotoxicity. We found that KA impaired mitochondrial morphology and led to impaired mitochondrial energy metabolism and dysfunction. In Western blotting experiments, KA disrupted mitochondrial quality control. In Nissl staining and CCK8 experiments, Mito-apocynin attenuated the death of neurons due to excitotoxic damage induced by KA both in vivo and in vitro. Mito-apocynin ameliorated neurobehavior induced by KA deficits in vivo and mitochondrial dysfunction in vitro. Mito-apocynin significantly reversed the increase in NOX4 levels caused by KA in the mitochondria of the striatum, decreased phosphorylated DRP1 (Ser616)/total DRP1 and increased PGC-1α, PINK1 and Parkin protein expression in the total striatum. In summary, Mito-apocynin alleviated oxidative stress, maintained normal mitochondrial function and energy metabolism levels, and promoted the balance of mitochondrial quality control by regulating the expression of NOX in mitochondria, thus reducing KA-induced excitatory toxic damage.
Excitotoxicity is a prevalent pathological event in neurodegenerative diseases. The involvement of ferroptosis in the pathogenesis of excitotoxicity remains elusive. Transcriptome analysis has revealed that cytoplasmic reduced nicotinamide adenine dinucleotide phosphate (NADPH) levels are associated with susceptibility to ferroptosis-inducing compounds. Here we show that exogenous NADPH, besides being reductant, interacts with N-myristoyltransferase 2 (NMT2) and upregulates the N-myristoylated ferroptosis suppressor protein 1 (FSP1). NADPH increases membrane-localized FSP1 and strengthens resistance to ferroptosis. Arg-291 of NMT2 is critical for the NADPH-NMT2-FSP1 axis-mediated suppression of ferroptosis. This study suggests that NMT2 plays a pivotal role by bridging NADPH levels and neuronal susceptibility to ferroptosis. We propose a mechanism by which the NADPH regulates N-myristoylation, which has important implications for ferroptosis and disease treatment.
Excitotoxicity refers to the ability of excessive extracellular excitatory amino acids to damage neurons via receptor activation. It is a crucial pathogenetic process in neurodegenerative diseases. TP53 is confirmed to be involved in excitotoxicity. It is demonstrated that TP53 induced glycolysis and apoptotic regulator (TIGAR)-regulated metabolic pathway can protect against neuronal injury. However, the role of TIGAR in excitotoxicity and specific mechanisms is still unknown. In this study, an in vivo excitotoxicity model was constructed via stereotypical kainic acid (KA) injection into the striatum of mice. KA reduced TIGAR expression levels, neuroinflammatory responses and mitochondrial dysfunction. TIGAR overexpression could reverse KA-induced neuronal injury by reducing neuroinflammation and improving mitochondrial function, thereby exerting neuroprotective effects. Therefore, this study could provide a potential therapeutic target for neurodegenerative diseases.
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