ArticleAdvanced science (Weinheim, Baden-Wurttemberg, Germany)2024
Metabolic Bypass Rescues Aberrant S-nitrosylation-Induced TCA Cycle Inhibition and Synapse Loss in Alzheimer's Disease Human Neurons.
Article in Advanced science (Weinheim, Baden-Wurttemberg, Germany), 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers, 1 of them a synthesis that pooled it.
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Who cites it
26 citing papers in PubMed, 1 synthesis or guideline pooled it, 18 citations in OpenAlex.
- Mitochondrial enzyme dysfunction in Alzheimer's disease: a systematic review of human metabolic evidence.Metabolic brain disease · 2026Pooled it
- Glutamine metabolism in health and disease.Signal transduction and targeted therapy · 2026Review
- Aberrant protein S-nitrosylation disrupts axonal development and metabolic homeostasis in a Cntnap2 mouse model of autism.Redox biology · 2026Article
- DLST Succinylation-Mediated Mitochondrial Metabolic Remodeling and Cuproptosis Resistance Promote Malignant Progression of Lung Adenocarcinoma.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Iron Deficiency Impairs Mitochondrial Energetics and Early Axonal Growth and Branching in Developing Hippocampal Neurons.The Journal of nutrition · 2026Article
- Electroacupuncture Improves the Learning and Memory by Modulating Hippocampal Glucose Metabolism through IGF1/IGF1R Signaling in Alzheimer's Disease.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Kinsenoside Targets IDH1 to Restore Microglial Immune-Metabolic Homeostasis for Alzheimer's Disease Therapy.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Metabolic modulation of TCA cycle bySynthetic and systems biotechnology · 2026Article
- Proteome-wide profiling of S-nitrosylated proteins using the SNOTRAP probe and mass spectrometry-based detection.Nature protocols · 2026Review
- Odd-Chain Fatty Acids-Enriched Algal Oil Improves Locomotor Function and Modulates Metabolic Pathways inMolecules (Basel, Switzerland) · 2026Article
- Aberrant Protein S-Nitrosylation Mimics the Effect of Rare Genetic Mutations in Neurodegenerative Diseases.Journal of neurochemistry · 2026Review
- Article
- Metabolomic Discoveries for Traditional Chinese Medicine Efficacy in Alzheimer's Disease.BioMed research international · 2026Review
- Unbiased distance correlation with sample-size-aware confidence bounds for comparative omics network analysis.Frontiers in bioinformatics · 2026Article
- Iron Deficiency Impairs Mitochondrial Energetics and Early Axonal Growth and Branching in Developing Hippocampal Neurons.bioRxiv : the preprint server for biology · 2025Article
- Aberrant S-nitrosylation in the TCA cycle contributes to mitochondrial dysfunction, energy compromise, and synapse loss in neurodegenerative diseases.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2025Review
- Redox modulation of the complement cascade contributes to synapse loss in Alzheimer's disease.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2025Review
- Polyphenol-rich Morus nigra L. extract mitigates neuroinflammation and cognitive impairment through gut-brain axis modulation in an Alzheimer's disease rat model.Frontiers in pharmacology · 2025Article
- Redox regulation, protein S-nitrosylation, and synapse loss in Alzheimer's and related dementias.Neuron · 2024Review
- Unveiling the molecular mechanisms of Danggui-Shaoyao-San against Alzheimer's disease in APP/PS1 mice via integrating proteomic and metabolomic approaches.Alzheimer's research & therapy · 2024Article
Corrections and comments
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Authors and funding
13 authors at 3 institutions in 3 countries.
Funding
Abstract
In Alzheimer's disease (AD), dysfunctional mitochondrial metabolism is associated with synaptic loss, the major pathological correlate of cognitive decline. Mechanistic insight for this relationship, however, is still lacking. Here, comparing isogenic wild-type and AD mutant human induced pluripotent stem cell (hiPSC)-derived cerebrocortical neurons (hiN), evidence is found for compromised mitochondrial energy in AD using the Seahorse platform to analyze glycolysis and oxidative phosphorylation (OXPHOS). Isotope-labeled metabolic flux experiments revealed a major block in activity in the tricarboxylic acid (TCA) cycle at the α-ketoglutarate dehydrogenase (αKGDH)/succinyl coenzyme-A synthetase step, metabolizing α-ketoglutarate to succinate. Associated with this block, aberrant protein S-nitrosylation of αKGDH subunits inhibited their enzyme function. This aberrant S-nitrosylation is documented not only in AD-hiN but also in postmortem human AD brains versus controls, as assessed by two separate unbiased mass spectrometry platforms using both SNOTRAP identification of S-nitrosothiols and chemoselective-enrichment of S-nitrosoproteins. Treatment with dimethyl succinate, a cell-permeable derivative of a TCA substrate downstream to the block, resulted in partial rescue of mitochondrial bioenergetic function as well as reversal of synapse loss in AD-hiN. These findings have therapeutic implications that rescue of mitochondrial energy metabolism can ameliorate synaptic loss in hiPSC-based models of AD.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.