Mitochondrial biogenesis in developing astrocytes regulates astrocyte maturation and synapse formation

Cell Rep. 2021 Apr 13;35(2):108952. doi: 10.1016/j.celrep.2021.108952.


The mechanisms controlling the post-natal maturation of astrocytes play a crucial role in ensuring correct synaptogenesis. We show that mitochondrial biogenesis in developing astrocytes is necessary for coordinating post-natal astrocyte maturation and synaptogenesis. The astrocytic mitochondrial biogenesis depends on the transient upregulation of metabolic regulator peroxisome proliferator-activated receptor gamma (PPARγ) co-activator 1α (PGC-1α), which is controlled by metabotropic glutamate receptor 5 (mGluR5). At tissue level, the loss or downregulation of astrocytic PGC-1α sustains astrocyte proliferation, dampens astrocyte morphogenesis, and impairs the formation and function of neighboring synapses, whereas its genetic re-expression is sufficient to restore the mitochondria compartment and correct astroglial and synaptic defects. Our findings show that the developmental enhancement of mitochondrial biogenesis in astrocytes is a critical mechanism controlling astrocyte maturation and supporting synaptogenesis, thus suggesting that astrocytic mitochondria may be a therapeutic target in the case of neurodevelopmental and psychiatric disorders characterized by impaired synaptogenesis.

Keywords: PGC-1α; astrocyte; mGluR5; mitochondria.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Astrocytes / cytology
  • Astrocytes / metabolism*
  • Brain / cytology
  • Brain / growth & development
  • Brain / metabolism
  • Cell Differentiation
  • Cell Proliferation
  • Electron Transport Complex IV / genetics
  • Electron Transport Complex IV / metabolism
  • Gene Expression Regulation, Developmental
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Humans
  • Male
  • Mice
  • Mice, Transgenic
  • Mitochondria / genetics*
  • Mitochondria / metabolism
  • Mitochondria / ultrastructure
  • Mitochondrial Proton-Translocating ATPases / genetics
  • Mitochondrial Proton-Translocating ATPases / metabolism
  • Neurogenesis / genetics*
  • Organelle Biogenesis
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / genetics*
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / metabolism
  • Primary Cell Culture
  • Receptor, Metabotropic Glutamate 5 / genetics*
  • Receptor, Metabotropic Glutamate 5 / metabolism
  • Synapses / genetics
  • Synapses / metabolism*
  • Synapses / ultrastructure
  • Synaptic Transmission / genetics*


  • Grm5 protein, mouse
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Ppargc1a protein, mouse
  • Receptor, Metabotropic Glutamate 5
  • enhanced cyan fluorescent protein
  • Green Fluorescent Proteins
  • COX5B protein, human
  • Cox4i1 protein, mouse
  • Electron Transport Complex IV
  • ATP5A1 protein, mouse
  • Mitochondrial Proton-Translocating ATPases