{"doi":"10.1002/advs.202306469","title":"Metabolic Bypass Rescues Aberrant S‐nitrosylation‐Induced TCA Cycle Inhibition and Synapse Loss in Alzheimer's Disease Human Neurons","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.","journal":"Advanced Science","year":2024,"id":422791,"datarank":0.49983067652628066,"base_score":3.332204510175204,"endowment":3.332204510175204,"self_citation_contribution":0.49983067652628066,"citation_network_contribution":0.0,"self_endowment_contribution":0.49983067652628066,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":27,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9542,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1048889,"name":"Hongmei Yang","orcid":"0000-0002-9048-2546","position":1,"is_corresponding":false},{"id":424539,"name":"Paschalis‐Thomas Doulias","orcid":"0000-0001-7891-3131","position":2,"is_corresponding":false},{"id":300266,"name":"Nima Dolatabadi","orcid":null,"position":3,"is_corresponding":false},{"id":555431,"name":"Xu Zhang","orcid":"0000-0001-6075-6000","position":4,"is_corresponding":false},{"id":619377,"name":"Melissa Luevanos","orcid":null,"position":5,"is_corresponding":false},{"id":1173095,"name":"Mayra Blanco","orcid":null,"position":6,"is_corresponding":false},{"id":1217760,"name":"Christine Baal","orcid":null,"position":7,"is_corresponding":false},{"id":1217235,"name":"I Made Harimbawa Putra","orcid":"0000-0002-2020-6183","position":8,"is_corresponding":false},{"id":298845,"name":"Tomohiro Nakamura","orcid":"0000-0002-4246-7771","position":9,"is_corresponding":false},{"id":347872,"name":"Harry Ischiropoulos","orcid":"0000-0001-8284-5098","position":10,"is_corresponding":false},{"id":50416,"name":"Steven R. Tannenbaum","orcid":"0000-0003-1819-3181","position":11,"is_corresponding":false},{"id":292124,"name":"Stuart A. Lipton","orcid":"0000-0002-3490-1259","position":12,"is_corresponding":false},{"id":692643,"name":"Alexander Y. Andreyev","orcid":"0000-0002-9246-9943","position":0,"is_corresponding":true}],"reference_count":65,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:57:51.642883Z","pmid":"38235614","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}