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.