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In this study, we reveal a noncanonical mitochondrial function of astrocytic connexin 43 (Cx43) whereby it directly inhibits isocitrate dehydrogenase 3\u03b1 (IDH3\u03b1), thereby sustaining glycolytic metabolism and lactate production essential for neuronal excitability. Astrocyte-specific deletion of Cx43 in the prelimbic cortex (PrL) recapitulates hallmark depressive phenotypes, characterized by reduced lactate synthesis, diminished neuronal excitability, and depressive-like behaviors. Loss of Cx43 enhances IDH3\u03b1 activity, prompting a metabolic reprogramming from aerobic glycolysis toward oxidative phosphorylation (OXPHOS) driven by glutamine-fueled anaplerosis, resulting in suppressed glucose uptake and decreased lactate output. This metabolic impairment restricts astrocytic lactate supply, depriving neurons of a critical energetic substrate. Importantly, this reprogramming occurs independently of gap junction intercellular communication, as demonstrated using a channel function-deficient dominant-negative Cx43 mutant. Restoration of mitochondrial Cx43 in astrocytes rescues neuronal excitability and ameliorates depressive-like phenotypes. Collectively, our findings identify mitochondrial Cx43 as a vital regulator of IDH3\u03b1 activity, essential for astrocyte-neuron metabolic coupling, and highlight a promising target for therapeutic intervention in depression.<\/jats:p>","DOI":"10.1038\/s41419-025-08309-1","type":"journal-article","created":{"date-parts":[[2025,12,8]],"date-time":"2025-12-08T22:54:12Z","timestamp":1765234452000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Noncanonical role of astrocytic mitochondrial Cx43: suppressing IDH3\u03b1 to sustain glycolytic homeostasis against depression"],"prefix":"10.1038","volume":"17","author":[{"given":"Junrui","family":"Ye","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongyun","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ye","family":"Peng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shasha","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruifang","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuqi","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruolan","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenzhen","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xu","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenbin","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gang","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5142-1874","authenticated-orcid":false,"given":"Hongshuo","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhongping","family":"Feng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6406-9846","authenticated-orcid":false,"given":"Shifeng","family":"Chu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5363-2157","authenticated-orcid":false,"given":"Zhao","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-6442-8191","authenticated-orcid":false,"given":"Naihong","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,12,8]]},"reference":[{"key":"8309_CR1","doi-asserted-by":"publisher","first-page":"2299","DOI":"10.1016\/S0140-6736(18)31948-2","volume":"392","author":"GS Malhi","year":"2018","unstructured":"Malhi GS, Mann JJ. 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