ATP Synthase c-Subunit Leak Causes Aberrant Cellular Metabolism in Fragile X Syndrome

  • Cell. 2020 Sep 3;182(5):1170-1185.e9. doi: 10.1016/j.cell.2020.07.008.
Pawel Licznerski  1 ,  Han-A Park  2 ,  Harshvardhan Rolyan  3 ,  Rongmin Chen  3 ,  Nelli Mnatsakanyan  3 ,  Paige Miranda  3 ,  Morven Graham  4 ,  Jing Wu  3 ,  Nicole Cruz-Reyes  5 ,  Nikita Mehta  5 ,  Sana Sohail  5 ,  Jorge Salcedo  5 ,  Erin Song  5 ,  Charles Effman  5 ,  Samuel Effman  5 ,  Lucas Brandao  6 ,  Gulan N Xu  3 ,  Amber Braker  3 ,  Valentin K Gribkoff  7 ,  Richard J Levy  8 ,  Elizabeth A Jonas  9
Affiliations
  • 1. Department of Internal Medicine, Section of Endocrinology, Yale University School of Medicine, New Haven, CT 06511, USA. Electronic address: [email protected].
  • 2. Department of Internal Medicine, Section of Endocrinology, Yale University School of Medicine, New Haven, CT 06511, USA; Department of Human Nutrition and Hospitality Management, College of Human Environmental Sciences, The University of Alabama, Tuscaloosa, AL 35487, USA.
  • 3. Department of Internal Medicine, Section of Endocrinology, Yale University School of Medicine, New Haven, CT 06511, USA.
  • 4. Department of Cell Biology, Yale University School of Medicine, New Haven, CT 06520, USA.
  • 5. Marine Biological Laboratory, Woods Hole, MA 02543, USA.
  • 6. Department of Biology, Clark University, Worcester, MA 01610, USA.
  • 7. Department of Internal Medicine, Section of Endocrinology, Yale University School of Medicine, New Haven, CT 06511, USA; Marine Biological Laboratory, Woods Hole, MA 02543, USA.
  • 8. Department of Anesthesiology, Columbia University Medical Center, New York, NY 10032, USA.
  • 9. Department of Internal Medicine, Section of Endocrinology, Yale University School of Medicine, New Haven, CT 06511, USA; Marine Biological Laboratory, Woods Hole, MA 02543, USA. Electronic address: [email protected].
PMID: 32795412 DOI: 10.1016/j.cell.2020.07.008
Abstract

Loss of the gene (Fmr1) encoding Fragile X mental retardation protein (FMRP) causes increased mRNA translation and aberrant synaptic development. We find neurons of the Fmr1-/y mouse have a mitochondrial inner membrane leak contributing to a "leak metabolism." In human Fragile X syndrome (FXS) fibroblasts and in Fmr1-/y mouse neurons, closure of the ATP Synthase leak channel by mild depletion of its c-subunit or pharmacological inhibition normalizes stimulus-induced and constitutive mRNA translation rate, decreases lactate and key glycolytic and tricarboxylic acid (TCA) cycle enzyme levels, and triggers synapse maturation. FMRP regulates leak closure in wild-type (WT), but not FX synapses, by stimulus-dependent ATP Synthase β subunit translation; this increases the ratio of ATP Synthase enzyme to its c-subunit, enhancing ATP production efficiency and synaptic growth. In contrast, in FXS, inability to close developmental c-subunit leak prevents stimulus-dependent synaptic maturation. Therefore, ATP Synthase c-subunit leak closure encourages development and attenuates autistic behaviors.

Keywords
Fragile X syndrome; autism; autism syndrome; glycolysis; mitochondria; oxidative phosphorylation; permeability transition pore; protein synthesis; repetitive mouse behavior; synaptic development; synaptic plasticity.
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