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

Pawel Licznerski1, Han-A Park2, Harshvardhan Rolyan1

  • 1Department of Internal Medicine, Section of Endocrinology, Yale University School of Medicine, New Haven, CT 06511, USA.

Cell
|August 16, 2020
PubMed

Insights

Fragile X syndrome involves a mitochondrial leak that disrupts synaptic development. Closing this ATP synthase leak channel normalizes translation and promotes synapse maturation, potentially reducing autistic behaviors.

Area of Science:

  • Neuroscience
  • Biochemistry
  • Genetics

Background:

  • Fragile X syndrome (FXS) is caused by the loss of the Fragile X mental retardation protein (FMRP).
  • FMRP loss leads to increased mRNA translation and abnormal synaptic development.
  • FXS neurons exhibit a mitochondrial inner membrane leak, termed "leak metabolism."

Purpose of the Study:

  • To investigate the role of mitochondrial ATP synthase in FXS.
  • To determine if targeting the ATP synthase leak channel can ameliorate FXS cellular phenotypes.
  • To elucidate the mechanism by which FMRP regulates synaptic development via ATP synthase.

Main Methods:

  • Utilized Fmr1 knockout (Fmr1-/y) mouse neurons and human FXS fibroblasts.
  • Manipulated ATP synthase c-subunit levels and used pharmacological inhibitors.
  • Measured mRNA translation rates, enzyme levels (glycolysis, TCA cycle), and synaptic maturation markers.

Main Results:

  • Closure of the ATP synthase leak channel normalized mRNA translation and decreased metabolic enzyme levels in FXS models.
  • Inhibition of the leak triggered synapse maturation in both human and mouse FXS cells.
  • FMRP normally regulates ATP synthase function for stimulus-dependent synaptic growth; this regulation is impaired in FXS.

Conclusions:

  • Mitochondrial ATP synthase c-subunit leak is a key factor in FXS pathophysiology.
  • Targeting this leak channel offers a potential therapeutic strategy for FXS.
  • Restoring ATP synthase function promotes synaptic maturation and may attenuate autistic behaviors associated with FXS.
Keywords:
Fragile X syndromeautismautism syndromeglycolysismitochondriaoxidative phosphorylationpermeability transition poreprotein synthesisrepetitive mouse behaviorsynaptic developmentsynaptic plasticity

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