# Mitochondrial control of protein translation in Fragile X

> **NIH NIH R01** · YALE UNIVERSITY · 2022 · $581,909

## Abstract

Abstract
Loss of function of the gene (Fmr1) encoding Fragile X mental retardation protein (FMRP) results
in unregulated mRNA translation and aberrant synaptic morphology. We find that mitochondria in
neurons of the Fmr1-/y mouse have an inner membrane leak that undermines ATP synthesis and
contributes to a replicative phenotype that is a hallmark of immature, dividing cells. Previous work
in cardiomyocytes showed that developmental maturation is dependent on closure of a
mitochondrial membrane leak. We now find that mild depletion of ATP synthase c-subunit to
reduce the leak or inhibition of the c-subunit leak with ATP synthase interacting agents decreases
mRNA translation in Fmr1-/y mouse neurons and human fibroblasts. Leak inhibition alters
metabolism in favor of oxidative phosphorylation. The developmental metabolic switch may be
dependent on stimulus-induced phosphorylation of translation elongation factor 2 (EF2), an event
which is lacking in Fmr1-/y synapses. Our data support a role for mitochondrial inner membrane
efficiency in determining the rate and type of protein translation. We suggest that increased
oxidative phosphorylation efficiency induced by closure of the ATP synthase c-subunit leak
channel produces mitochondrial ATP in response to synaptic stimulation to phosphorylate EF2
and change the synaptic proteome. Thus, we will determine if pharmacological reagents that
decrease inner membrane leak will do so in recordings of mitochondria isolated from Fmr1-/y
synapses and if these reagents reverse the change in ATP synthase stoichiometry that causes
increased c-subunit expression and inner mitochondrial membrane leak in the Fmr1-/Y mouse
(Aim#1). We will assess synapse formation and plasticity (Aim #2) and behavior (Aim #3) following
closure of the leak in cultured neurons or in vivo using dexpramipexole (Dex) and CoQ10. Dex is
a cell death modulator that binds to the OSCP/b subunit of ATP synthase and closes the ATP
synthase leak without affecting the immune system. It readily crosses the blood brain barrier,
enhances ATP production in neurons and was recently studied in patients. Thus, both Dex and
CoQ10 have excellent translational potential if successful. Finally, we will cross breed Fmr1-/Y
mice with mice harboring a genetically modified ATP synthase c-subunit ring to determine if
genetic reduction of the inner membrane leak rescues the FX synaptic phenotype. We suggest
that FMRP regulates a stimulus-dependent change in mitochondrial metabolism required for
normal synaptic development and plasticity.

## Key facts

- **NIH application ID:** 10379427
- **Project number:** 5R01NS112706-04
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Kambiz Nassirpour Alavian
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $581,909
- **Award type:** 5
- **Project period:** 2019-06-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10379427

## Citation

> US National Institutes of Health, RePORTER application 10379427, Mitochondrial control of protein translation in Fragile X (5R01NS112706-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10379427. Licensed CC0.

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