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

Area of Science:

• Neuroscience
• Metabolic pathways
• Neuroinflammation

Background:

• Depression is a widespread neuropsychiatric disorder linked to metabolic dysfunction.
• Molecular mechanisms connecting metabolic pathways and depressive behavior are not well understood.

Purpose of the Study:

• To investigate the role of CDGSH iron sulfur domain 1 (CISD1) in the pathophysiology of depression.
• To elucidate the molecular mechanisms by which CISD1 influences microglial metabolism and depressive-like behavior.

Main Methods:

• Utilized mouse models of chronic stress and depression.
• Employed pharmacological inhibition and genetic knockdown of CISD1.
• Investigated CISD1 expression in the medial prefrontal cortex and microglia.
• Analyzed metabolic pathways including NADH oxidation and glycolysis.
• Assessed depressive-like behavior and microglial inflammatory activation.

Main Results:

• CISD1 is upregulated in the medial prefrontal cortex following chronic stress.
• Inhibition or knockdown of CISD1 ameliorates depressive-like behavior and reduces microglial inflammation.
• Chronic stress specifically increases microglial CISD1 expression.
• Microglial CISD1 knockout alleviates neuroinflammation and depressive-like behavior.
• CISD1 upregulation promotes NADH oxidation and NAD+ generation, enhancing glycolysis and inflammation.
• Pioglitazone's antidepressant effect involves inhibiting NADH oxidation via a CISD1-dependent microglial pathway.

Conclusions:

• CISD1 plays a critical role in microglial metabolism and neuroinflammation in depression.
• Targeting CISD1-dependent metabolic pathways in microglia offers a potential therapeutic strategy for depression.
• This study provides a foundation for developing novel antidepressant drugs.