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Updated: Jun 21, 2026
Functional Interrogation of Adult Hypothalamic Neurogenesis with Focal Radiological Inhibition
Published on: November 14, 2013
Gasdermin D Mediated Mitochondrial Metabolism Orchestrate Neurogenesis Through LDHA During Embryonic Development
Hongyan Ma1,2,3, Huiyang Jia1,2,3, Wenzheng Zou1,2,3
1Key Laboratory of Organ Regeneration and Reconstruction, State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Science, Beijing, 100101, China.
Abstract:
Regulatory cell death is an important way to eliminate the DNA damage that accompanies the rapid proliferation of neural stem cells during cortical development, including pyroptosis, apoptosis, and so on. Here, the study reports that the absence of GSDMD-mediated pyroptosis results in defective DNA damage sensor pathways accompanied by aberrant neurogenesis and autism-like behaviors in adult mice. Furthermore, GSDMD is involved in organizing the mitochondrial electron transport chain by regulating the AMPK/PGC-1α pathway to target Aifm3. This process promotes a switch from oxidative phosphorylation to glycolysis. The perturbation of metabolic homeostasis in neural progenitor cells increases lactate production which acts as a signaling molecule to regulate the p38MAPK pathway. And activates NF-𝜿B transcription to disrupt cortex development. This abnormal proliferation of neural progenitor cells can be rescued by inhibiting glycolysis and lactate production. Taken together, the study proposes a metabolic axis regulated by GSDMD that links pyroptosis with metabolic reprogramming. It provides a flexible perspective for the treatment of neurological disorders caused by genotoxic stress and neurodevelopmental disorders such as autism.
Insights
Pyroptosis, a form of cell death, is crucial for brain development. Its absence, due to GSDMD deficiency, leads to neurodevelopmental defects and autism-like behaviors in mice.
Area of Science:
- Neuroscience
- Cell Biology
- Developmental Biology
Background:
- Regulatory cell death, including pyroptosis, is essential for clearing DNA damage during neural stem cell proliferation in cortical development.
- Defects in DNA damage response pathways can lead to aberrant neurogenesis and neurodevelopmental disorders.
Purpose of the Study:
- To investigate the role of GSDMD-mediated pyroptosis in cortical development and its connection to metabolic homeostasis.
- To explore the potential of targeting metabolic pathways for treating neurodevelopmental disorders.
Main Methods:
- Utilized a mouse model lacking GSDMD-mediated pyroptosis.
- Analyzed DNA damage sensor pathways, neurogenesis, and mitochondrial function.
- Investigated metabolic pathways including oxidative phosphorylation, glycolysis, and lactate production.
- Examined the AMPK/PGC-1α pathway, Aifm3, p38MAPK, and NF-κB signaling.
Main Results:
- Absence of GSDMD-mediated pyroptosis resulted in defective DNA damage sensor pathways.
- GSDMD deficiency led to aberrant neurogenesis and autism-like behaviors in adult mice.
- GSDMD regulates mitochondrial electron transport chain organization via the AMPK/PGC-1α/Aifm3 axis, promoting a switch to glycolysis.
- Perturbed metabolic homeostasis and increased lactate production in neural progenitor cells disrupted cortex development via p38MAPK and NF-κB signaling.
- Inhibiting glycolysis and lactate production rescued abnormal neural progenitor cell proliferation.
Conclusions:
- GSDMD-mediated pyroptosis is critical for maintaining metabolic homeostasis and proper cortical development.
- A novel metabolic axis regulated by GSDMD links pyroptosis to metabolic reprogramming in neural progenitor cells.
- Targeting this GSDMD-regulated metabolic axis offers a potential therapeutic strategy for neurodevelopmental disorders, including autism, associated with genotoxic stress.
