Mitochondrial CISD1 Modulates Microglial Metabolic Reprogramming to Drive Stress Susceptibility in Mice

Abstract Depression is one of the most prevalent neuropsychiatric disorders worldwide, and multiple studies have implicated metabolic dysfunction in its pathophysiology. However, the molecular mechanisms by which metabolic pathways modulate depressive‑like behavior remain largely uncharacterized. Here, this work finds that the CDGSH iron sulfur domain 1 (CISD1), a redox protein localized to the outer mitochondrial membrane, is upregulated in the medial prefrontal cortex after chronic stress. Pharmacological inhibition and genetic knockdown of CISD1 significantly ameliorate depressive‐like behavior in mice, and CISD1 knockdown also reverse microglial inflammatory activation. Moreover, this work finds that chronic stress specifically upregulates microglial CISD1 expression, and that conditional knockout of microglial CISD1 alleviates neuroinflammation and depressive‑like behavior in mice. Mechanistically, chronic stress promotes NADH oxidation to generate NAD⁺ by upregulating CISD1 expression. The elevated NAD⁺ functions as a cofactor for glyceraldehyde‐3‐phosphate dehydrogenase, accelerating glycolysis and promoting inflammatory activation. Pioglitazone exerts antidepressant effects by inhibiting NADH oxidation through a CISD1‐dependent pathway in microglia. In conclusion, this study elucidates the role of CISD1 in microglial metabolism, establishing a robust experimental foundation for screening potential antidepressant drugs.