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MeCP2 dysregulation inhibits mitophagy and impairs neural development in cortical organoids

Jing Zhou1, Yuchun Liu2, Xintao Jing3

  • 1Department of Cell Biology and Genetics, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China; Central Laboratory, Jiangxi Provincial Children's Hospital, Nanchang, Jiangxi 330006, China.

Journal of Advanced Research
|July 22, 2025
PubMed
Abstract

Insights

Methylated CpG-binding protein 2 (MeCP2) regulates mitophagy by controlling BNIP3L gene expression. MeCP2 mutations impair mitophagy, causing mitochondrial issues and neurodevelopmental problems.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Genetics

Background:

  • Methylated CpG-binding protein 2 (MeCP2) is crucial for nervous system development.
  • Mutations in MeCP2 are linked to neurodevelopmental disorders, potentially due to mitochondrial dysfunction and impaired mitophagy.
  • The precise mechanisms linking MeCP2 dysfunction to these disorders are not fully understood.

Purpose of the Study:

  • To investigate how MeCP2 regulates mitophagy.
  • To explore the molecular mechanisms underlying MeCP2's role in mitophagy.
  • To determine how MeCP2 dysfunction contributes to neurodevelopmental abnormalities using human cortical organoids.

Main Methods:

  • Generated MeCP2 mutant induced pluripotent stem cells (iPSCs) using CRISPR-Cas9.
  • Differentiated iPSCs into cortical organoids (COs).
  • Analyzed neural stem cell growth, proliferation, differentiation, and gene expression via single-cell RNA sequencing, focusing on mitophagy genes and MeCP2 binding at the BNIP3L promoter.

Main Results:

  • MeCP2 mutant COs showed growth inhibition, abnormal proliferation, and disrupted neural stem cell differentiation.
  • Single-cell RNA sequencing identified significant downregulation of the mitophagy receptor BNIP3L in mutant COs.
  • MeCP2 was found to bind to the BNIP3L transcription start site, suppressing its expression and impairing mitophagy.

Conclusions:

  • MeCP2 regulates mitophagy by modulating BNIP3L expression.
  • MeCP2 dysfunction leads to mitochondrial accumulation and neurodevelopmental abnormalities.
  • This study elucidates MeCP2's role in mitochondrial homeostasis and provides insights into MeCP2-related neurodevelopmental disorders.
Keywords:
BNIP3LCortical organoidsMeCP2MitophagyNeural development

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