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.
Tamara Zehnder  1 ,  Francesco Petrelli  1 ,  Jennifer Romanos  2 ,  Eva C De Oliveira Figueiredo  1 ,  Tommy L Lewis Jr  3 ,  Nicole Déglon  4 ,  Franck Polleux  3 ,  Mirko Santello  5 ,  Paola Bezzi  6
Affiliations
  • 1. Department of Fundamental Neurosciences, Faculty of Biology and Medicine, University of Lausanne, Rue du Bugnon 9, 1005 Lausanne, Switzerland.
  • 2. Institute of Pharmacology and Toxicology, University of Zurich, 8057 Zurich, Switzerland.
  • 3. Department of Neuroscience, Columbia University, New York, NY 10032, USA; Mortimer B. Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY 10032, USA.
  • 4. Department of Clinical Neurosciences, Laboratory of Neurotherapies and Neuromodulation (LNTM), Lausanne University Hospital (CHUV) and University of Lausanne, 1011 Lausanne, Switzerland; Neurosciences Research Center (CRN), Laboratory of Neurotherapies and Neuromodulation (LNTM), Lausanne University Hospital and University of Lausanne, 1011 Lausanne, Switzerland.
  • 5. Institute of Pharmacology and Toxicology, University of Zurich, 8057 Zurich, Switzerland. Electronic address: [email protected].
  • 6. Department of Fundamental Neurosciences, Faculty of Biology and Medicine, University of Lausanne, Rue du Bugnon 9, 1005 Lausanne, Switzerland; Department of Physiology and Pharmacology, Sapienza University of Rome, 00185 Rome, Italy. Electronic address: [email protected].
PMID: 33852851 DOI: 10.1016/j.celrep.2021.108952
Abstract

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.
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