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

## TL;DR

This study shows that the protein CISD1 in microglia affects metabolism and inflammation, contributing to depression-like behavior in mice under stress.

## Contribution

The study identifies CISD1 as a novel regulator of microglial metabolic reprogramming linked to stress-induced depression.

## Key findings

- CISD1 upregulation in microglia under chronic stress increases NAD⁺ and glycolysis, promoting inflammation.
- Knocking down CISD1 in microglia reduces neuroinflammation and depressive-like behavior in mice.
- Pioglitazone exerts antidepressant effects by inhibiting CISD1-dependent NADH oxidation.

## 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.

CDGSH iron sulfur domain 1 (CISD1) mitigates oxidative stress by promoting NADH oxidation and Coenzyme Q (CoQ) reduction. Under chronic stress, elevated CISD1 expression in microglia enhances NAD⁺ production, thereby increasing GAPDH activity and glycolytic flux, while reducing ATP synthesis by inhibiting proton transfer from mitochondrial complexes I and II to CoQ. These metabolic alterations collectively drive microglial inflammatory activation.