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<p>Depression remains a pervasive global health challenge, compounded by limited therapeutic efficacy that is partly attributed to incompletely understood metabolic underpinnings. In this study, we reveal a noncanonical mitochondrial function of astrocytic connexin 43 (Cx43) whereby it directly inhibits isocitrate dehydrogenase 3α (IDH3α), 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 IDH3α 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 IDH3α activity, essential for astrocyte-neuron metabolic coupling, and highlight a promising target for therapeutic intervention in depression.</p>

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Noncanonical role of astrocytic mitochondrial Cx43: suppressing IDH3α to sustain glycolytic homeostasis against depression

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月8日

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  • Junrui Ye,
  • Hongyun Wang,
  • Ye Peng,
  • Shasha Wang,
  • Ruifang Zheng,
  • Yuqi Chen,
  • Ruolan Yuan,
  • Zhenzhen Wang,
  • Xu Yan,
  • Wenbin He,
  • Gang Li,
  • Hongshuo Sun,
  • Zhongping Feng,
  • Shifeng Chu,
  • Zhao Zhang,
  • Naihong Chen

摘要

Depression remains a pervasive global health challenge, compounded by limited therapeutic efficacy that is partly attributed to incompletely understood metabolic underpinnings. In this study, we reveal a noncanonical mitochondrial function of astrocytic connexin 43 (Cx43) whereby it directly inhibits isocitrate dehydrogenase 3α (IDH3α), 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 IDH3α 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 IDH3α activity, essential for astrocyte-neuron metabolic coupling, and highlight a promising target for therapeutic intervention in depression.