RRC ID 82757
Author Ma H, Jia H, Zou W, Ji F, Wang W, Zhao J, Yuan C, Jiao J.
Title Gasdermin D Mediated Mitochondrial Metabolism Orchestrate Neurogenesis Through LDHA During Embryonic Development.
Journal Adv Sci (Weinh)
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.
Volume 11(35)
Pages e2402285
Published 2024-9-1
DOI 10.1002/advs.202402285
PMID 39033542
PMC PMC11425199
MeSH Animals Disease Models, Animal Embryonic Development* / genetics Embryonic Development* / physiology Gasdermins Intracellular Signaling Peptides and Proteins* / genetics Intracellular Signaling Peptides and Proteins* / metabolism Lactate Dehydrogenase 5 / genetics Lactate Dehydrogenase 5 / metabolism Mice Mitochondria* / metabolism Neural Stem Cells / metabolism Neurogenesis* / physiology Phosphate-Binding Proteins* / genetics Phosphate-Binding Proteins* / metabolism Signal Transduction
Resource
Mice RBRC10762