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• W3097452302 abstract "Recent work by Licznerski et al. suggests that mutant FMRP linked to Fragile-X syndrome elevates the inner mitochondrial membrane proton leak, leading to increased metabolism and changes in protein synthesis that trigger impaired synaptic maturation and autistic behaviors. Recent work by Licznerski et al. suggests that mutant FMRP linked to Fragile-X syndrome elevates the inner mitochondrial membrane proton leak, leading to increased metabolism and changes in protein synthesis that trigger impaired synaptic maturation and autistic behaviors. Main TextFragile-X syndrome is the most common form of inherited intellectual disability with severe, pervasive neurologic symptoms including autism, motor dysfunction, and increased risk of epilepsy. Fragile-X syndrome is caused by loss-of-function mutations in the Fragile X mental retardation (FMR1) gene located on the X chromosome. It is not fully understood how FMR1 mutations impair brain function. Previous studies have linked mitochondrial dysfunction to Fragile-X syndrome. Recently, Licznerski et al. demonstrate that proton leak within the inner mitochondrial membrane is a causal link between abnormal mitochondrial function and Fragile-X-syndrome-related neuronal phenotypes.The FMR1 gene is disrupted by expansion of a CGG triplet repeat sequence, which results in DNA hypermethylation and silencing of FMR1 when the repeats exceed 200 copies. Alternatively, in a small minority of cases, FMR1 may be absent or lack function for other reasons, but in all cases the FMR1 gene product Fragile-X Mental Retardation Protein (FMRP) is deficient. Most theories of Fragile-X pathophysiology are centered on the seminal finding that FMRP is clearly an RNA binding protein that regulates diverse components of the synapse, many of which are implicated in neuropsychiatric disease (Darnell et al., 2011Darnell J.C. Van Driesche S.J. Zhang C. Hung K.Y. Mele A. Fraser C.E. Stone E.F. Chen C. Fak J.J. Chi S.W. et al.FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism.Cell. 2011; 146: 247-261Abstract Full Text Full Text PDF PubMed Scopus (1377) Google Scholar). Mice deficient for Fmr1 develop symptomatology and histopathology consistent with human Fragile-X disease, including abnormal synapse development (Bassell and Warren, 2008Bassell G.J. Warren S.T. Fragile X syndrome: loss of local mRNA regulation alters synaptic development and function.Neuron. 2008; 60: 201-214Abstract Full Text Full Text PDF PubMed Scopus (794) Google Scholar). Studies of the Fmr1 knockout mouse (Fmr1-/y) gave rise to a central theory that rapid activity-dependent protein synthesis, which is critical for synaptic plasticity, is impaired in Fragile-X syndrome (Bear et al., 2004Bear M.F. Huber K.M. Warren S.T. The mGluR theory of fragile X mental retardation.Trends Neurosci. 2004; 27: 370-377Abstract Full Text Full Text PDF PubMed Scopus (1256) Google Scholar). As wild-type (WT) FMRP inhibits protein synthesis, in Fragile-X the unfettered expression of proteins is thought to interfere with more specific mechanisms that control synaptic development.An interesting aspect of the Fmr1-/y mice is that the impairment of synaptic maturation is associated with abnormal mitochondrial fusion (Shen et al., 2019Shen M. Wang F. Li M. Sah N. Stockton M.E. Tidei J.J. Gao Y. Korabelnikov T. Kannan S. Vevea J.D. et al.Reduced mitochondrial fusion and Huntingtin levels contribute to impaired dendritic maturation and behavioral deficits in Fmr1-mutant mice.Nat Neurosci. 2019; 22: 386-400Crossref PubMed Scopus (38) Google Scholar) and deficiencies in oxidative phosphorylation with preserved ATP production (D’Antoni et al., 2020D’Antoni S. de Bari L. Valenti D. Borro M. Bonaccorso C.M. Simmaco M. Vacca R.A. Catania M.V. Aberrant mitochondrial bioenergetics in the cerebral cortex of the Fmr1 knockout mouse model of fragile X syndrome.Biol Chem. 2020; 401: 497-503Crossref PubMed Scopus (24) Google Scholar). Furthermore, recent work demonstrated an abnormal proton leak in Fmr1-/y mitochondria when analyzing state 4 of mitochondrial respiration (Griffiths et al., 2020Griffiths K.K. Wang A. Wang L. Tracey M. Kleiner G. Quinzii C.M. Sun L. Yang G. Perez-Zoghbi J.F. Licznerski P. et al.Inefficient thermogenic mitochondrial respiration due to futile proton leak in a mouse model of fragile X syndrome.FASEB J. 2020; 34: 7404-7426Crossref PubMed Scopus (16) Google Scholar). The proton leak in Fmr1-/y mitochondria could be corrected by pharmacologic manipulations, which resulted in resolution of Fragile-X symptoms (Griffiths et al., 2020Griffiths K.K. Wang A. Wang L. Tracey M. Kleiner G. Quinzii C.M. Sun L. Yang G. Perez-Zoghbi J.F. Licznerski P. et al.Inefficient thermogenic mitochondrial respiration due to futile proton leak in a mouse model of fragile X syndrome.FASEB J. 2020; 34: 7404-7426Crossref PubMed Scopus (16) Google Scholar). Now work by Licznerski and colleagues addresses a missing, but crucial, mechanism for how FMRP loss causes the abnormal mitochondrial proton leak to impair synaptic plasticity (Licznerski et al., 2020Licznerski P. Park H.A. Rolyan H. Chen R. Mnatsakanyan N. Miranda P. Graham M. Wu J. Cruz-Reyes N. Mehta N. et al ATP Synthase c-Subunit Leak Causes Aberrant Cellular Metabolism in Fragile X Syndrome..Cell. 2020; 182: 1170-1185Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar). Using a combination of genetic and pharmacologic techniques in the Fmr1-/y mice, Licznerski and colleagues examined the proton leak within Fmr1-deficient neurons to show an abnormal metabolic phenotype that can be reversed pharmacologically. Importantly, they demonstrate both in vivo and behavioral findings from Fmr1-/y mice that validate the possibility of the proton leak as a causal link between abnormal mitochondrial function and Fragile-X-related neuronal phenotypes.In the first set of experiments, the authors find that in vitro mitochondrial membrane potential is approximately half of WT, a phenomenon potentially attributable to proton leak. Prior work by the group had shown that dexpramipexole (DEX) was able to block inner membrane leak activity by binding to ATP synthase (Alavian et al., 2015Alavian K.N. Dworetzky S.I. Bonanni L. Zhang P. Sacchetti S. Li H. Signore A.P. Smith P.J. Gribkoff V.K. Jonas E.A. The mitochondrial complex V-associated large-conductance inner membrane current is regulated by cyclosporine and dexpramipexole.Mol Pharmacol. 2015; 87: 1-8Crossref PubMed Scopus (34) Google Scholar). Using patch clamping of Fmr1-/y mitochondrial membranes, they demonstrate an abnormal conductance that DEX reduces. The findings strongly implicate ATP synthase itself as the source of a proton leak in Fmr1-/y mitochondria. By analyzing subunits of the ATP synthase, the authors conclude that Fmr1-/y mitochondria have similar levels of assembled ATP synthase compared to WT but elevated free c-subunit of ATP synthase that contributes to the increase in proton leak (Figure 1).Turning to the functional aspects of the identified inner membrane proton leak, the authors attempt to profile the metabolic phenotype of Fmr1-/y neurons as compared to WT. They observe increased flux through glycolysis concomitant with elevated lactate production in Fmr1-/y neurons compared to WT neurons. Interestingly, they also observe an increase in tricarboxylic acid (TCA) cycle flux in the Fmr1-/y neurons. A coordinate increase in glycolysis and TCA cycle is indicative of anabolism (DeBerardinis and Chandel, 2020DeBerardinis R.J. Chandel N.S. We need to talk about the Warburg effect.Nat Metab. 2020; 2: 127-129Crossref PubMed Scopus (227) Google Scholar) that is a salient feature of immature and developing neurons. The addition of DEX reduces glycolytic and TCA flux, indicating that elevated proton leak controls metabolic phenotype of Fmr1-/y neurons. The mechanisms underlying how the proton leak control increases anabolism in Fmr1-/y neurons remains unclear. A rate-limiting step in controlling glycolysis and TCA cycle flux is the availability of nicotinamide adenine dinucleotide (NAD+), which is generated by mitochondrial complex I. An elevated proton leak will increase the ability of mitochondrial complex I to regenerate NAD+, thus increasing glycolysis and TCA cycle (Figure 1).A cardinal feature of Fragile-X is increased mRNA translation, which results in elevated protein synthesis rates. Licznerski et al. demonstrate that DEX or small interfering RNA (siRNA) directed to the c-subunit of ATP synthase were able to reduce protein synthesis Fmr1-/y neurons. By contrast, the overexpression of c-subunit in Fmr1-/y neurons increased protein synthesis. Collectively, these experiments indicate that the c-subunit-dependent proton leak is required and sufficient to increase protein synthesis rates in Fmr1-/y neurons. How proton leak controls protein synthesis remains unknown. Previous studies in Fmr1-/y mice have demonstrated hyperactivation of two pathways that control protein synthesis, the mTORC1 (mechanistic target of rapamycin complex I) and MAPK/ERK (mitogen-activated protein kinase/extracellular signal-regulated kinase) pathways (Gantois et al., 2019Gantois I. Popic J. Khoutorsky A. Sonenberg N. Metformin for Treatment of Fragile X Syndrome and Other Neurological Disorders.Annu Rev Med. 2019; 70: 167-181Crossref PubMed Scopus (36) Google Scholar). It would be of interest to know if these pathways are connected to the c-subunit-dependent proton leak. One simple explanation might be that the proton leak increases levels of glycolytic and TCA cycle metabolites that are known to hyperactivate mTORC1, leading to enhanced protein synthesis and impaired synaptic development (Figure 1).To connect the abnormal protein synthesis with Fragile-X pathophysiology, the authors turn to neuronal-stimulation-dependent rapid protein expression. With this model, excitatory stimulation of WT synaptosomes results in rapid initiation of protein synthesis that is absent in Fmr1-/y-derived synaptosomes. The phenomenon in Fmr1-/y is effectively reversed by pharmacologic closure of the proton leak. The authors are also able to demonstrate that changes in ATP synthase subunit expression are sensitive to neuronal activity and are restored to WT patterns with closure of the proton leak. Importantly, the authors use an in vivo model to investigate whether the proton leak has any impact on the neurobehavioral phenotype of Fmr1-/y mice. By injecting DEX, the authors demonstrate normalization of some behaviors (grooming, nestlet shredding, hyperactivity) without altering the behavior of WT mice (Figure 1). Going forward, an important genetic validation of the DEX experiment would be to genetically diminish the c-subunit and cross them to Fmr1-/y mice.Together, the experimental evidence provided by Licznerski and colleagues shed light on a potentially treatable pathway for Fragile-X syndrome. Applying the findings generated by Licznerski et al. to connect the proton leak and increase in metabolism to synaptic plasticity for Fragile-X syndrome opens up future research on metabolic dysregulation as a driver of neurological pathologies. Main TextFragile-X syndrome is the most common form of inherited intellectual disability with severe, pervasive neurologic symptoms including autism, motor dysfunction, and increased risk of epilepsy. Fragile-X syndrome is caused by loss-of-function mutations in the Fragile X mental retardation (FMR1) gene located on the X chromosome. It is not fully understood how FMR1 mutations impair brain function. Previous studies have linked mitochondrial dysfunction to Fragile-X syndrome. Recently, Licznerski et al. demonstrate that proton leak within the inner mitochondrial membrane is a causal link between abnormal mitochondrial function and Fragile-X-syndrome-related neuronal phenotypes.The FMR1 gene is disrupted by expansion of a CGG triplet repeat sequence, which results in DNA hypermethylation and silencing of FMR1 when the repeats exceed 200 copies. Alternatively, in a small minority of cases, FMR1 may be absent or lack function for other reasons, but in all cases the FMR1 gene product Fragile-X Mental Retardation Protein (FMRP) is deficient. Most theories of Fragile-X pathophysiology are centered on the seminal finding that FMRP is clearly an RNA binding protein that regulates diverse components of the synapse, many of which are implicated in neuropsychiatric disease (Darnell et al., 2011Darnell J.C. Van Driesche S.J. Zhang C. Hung K.Y. Mele A. Fraser C.E. Stone E.F. Chen C. Fak J.J. Chi S.W. et al.FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism.Cell. 2011; 146: 247-261Abstract Full Text Full Text PDF PubMed Scopus (1377) Google Scholar). Mice deficient for Fmr1 develop symptomatology and histopathology consistent with human Fragile-X disease, including abnormal synapse development (Bassell and Warren, 2008Bassell G.J. Warren S.T. Fragile X syndrome: loss of local mRNA regulation alters synaptic development and function.Neuron. 2008; 60: 201-214Abstract Full Text Full Text PDF PubMed Scopus (794) Google Scholar). Studies of the Fmr1 knockout mouse (Fmr1-/y) gave rise to a central theory that rapid activity-dependent protein synthesis, which is critical for synaptic plasticity, is impaired in Fragile-X syndrome (Bear et al., 2004Bear M.F. Huber K.M. Warren S.T. The mGluR theory of fragile X mental retardation.Trends Neurosci. 2004; 27: 370-377Abstract Full Text Full Text PDF PubMed Scopus (1256) Google Scholar). As wild-type (WT) FMRP inhibits protein synthesis, in Fragile-X the unfettered expression of proteins is thought to interfere with more specific mechanisms that control synaptic development.An interesting aspect of the Fmr1-/y mice is that the impairment of synaptic maturation is associated with abnormal mitochondrial fusion (Shen et al., 2019Shen M. Wang F. Li M. Sah N. Stockton M.E. Tidei J.J. Gao Y. Korabelnikov T. Kannan S. Vevea J.D. et al.Reduced mitochondrial fusion and Huntingtin levels contribute to impaired dendritic maturation and behavioral deficits in Fmr1-mutant mice.Nat Neurosci. 2019; 22: 386-400Crossref PubMed Scopus (38) Google Scholar) and deficiencies in oxidative phosphorylation with preserved ATP production (D’Antoni et al., 2020D’Antoni S. de Bari L. Valenti D. Borro M. Bonaccorso C.M. Simmaco M. Vacca R.A. Catania M.V. Aberrant mitochondrial bioenergetics in the cerebral cortex of the Fmr1 knockout mouse model of fragile X syndrome.Biol Chem. 2020; 401: 497-503Crossref PubMed Scopus (24) Google Scholar). Furthermore, recent work demonstrated an abnormal proton leak in Fmr1-/y mitochondria when analyzing state 4 of mitochondrial respiration (Griffiths et al., 2020Griffiths K.K. Wang A. Wang L. Tracey M. Kleiner G. Quinzii C.M. Sun L. Yang G. Perez-Zoghbi J.F. Licznerski P. et al.Inefficient thermogenic mitochondrial respiration due to futile proton leak in a mouse model of fragile X syndrome.FASEB J. 2020; 34: 7404-7426Crossref PubMed Scopus (16) Google Scholar). The proton leak in Fmr1-/y mitochondria could be corrected by pharmacologic manipulations, which resulted in resolution of Fragile-X symptoms (Griffiths et al., 2020Griffiths K.K. Wang A. Wang L. Tracey M. Kleiner G. Quinzii C.M. Sun L. Yang G. Perez-Zoghbi J.F. Licznerski P. et al.Inefficient thermogenic mitochondrial respiration due to futile proton leak in a mouse model of fragile X syndrome.FASEB J. 2020; 34: 7404-7426Crossref PubMed Scopus (16) Google Scholar). Now work by Licznerski and colleagues addresses a missing, but crucial, mechanism for how FMRP loss causes the abnormal mitochondrial proton leak to impair synaptic plasticity (Licznerski et al., 2020Licznerski P. Park H.A. Rolyan H. Chen R. Mnatsakanyan N. Miranda P. Graham M. Wu J. Cruz-Reyes N. Mehta N. et al ATP Synthase c-Subunit Leak Causes Aberrant Cellular Metabolism in Fragile X Syndrome..Cell. 2020; 182: 1170-1185Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar). Using a combination of genetic and pharmacologic techniques in the Fmr1-/y mice, Licznerski and colleagues examined the proton leak within Fmr1-deficient neurons to show an abnormal metabolic phenotype that can be reversed pharmacologically. Importantly, they demonstrate both in vivo and behavioral findings from Fmr1-/y mice that validate the possibility of the proton leak as a causal link between abnormal mitochondrial function and Fragile-X-related neuronal phenotypes.In the first set of experiments, the authors find that in vitro mitochondrial membrane potential is approximately half of WT, a phenomenon potentially attributable to proton leak. Prior work by the group had shown that dexpramipexole (DEX) was able to block inner membrane leak activity by binding to ATP synthase (Alavian et al., 2015Alavian K.N. Dworetzky S.I. Bonanni L. Zhang P. Sacchetti S. Li H. Signore A.P. Smith P.J. Gribkoff V.K. Jonas E.A. The mitochondrial complex V-associated large-conductance inner membrane current is regulated by cyclosporine and dexpramipexole.Mol Pharmacol. 2015; 87: 1-8Crossref PubMed Scopus (34) Google Scholar). Using patch clamping of Fmr1-/y mitochondrial membranes, they demonstrate an abnormal conductance that DEX reduces. The findings strongly implicate ATP synthase itself as the source of a proton leak in Fmr1-/y mitochondria. By analyzing subunits of the ATP synthase, the authors conclude that Fmr1-/y mitochondria have similar levels of assembled ATP synthase compared to WT but elevated free c-subunit of ATP synthase that contributes to the increase in proton leak (Figure 1).Turning to the functional aspects of the identified inner membrane proton leak, the authors attempt to profile the metabolic phenotype of Fmr1-/y neurons as compared to WT. They observe increased flux through glycolysis concomitant with elevated lactate production in Fmr1-/y neurons compared to WT neurons. Interestingly, they also observe an increase in tricarboxylic acid (TCA) cycle flux in the Fmr1-/y neurons. A coordinate increase in glycolysis and TCA cycle is indicative of anabolism (DeBerardinis and Chandel, 2020DeBerardinis R.J. Chandel N.S. We need to talk about the Warburg effect.Nat Metab. 2020; 2: 127-129Crossref PubMed Scopus (227) Google Scholar) that is a salient feature of immature and developing neurons. The addition of DEX reduces glycolytic and TCA flux, indicating that elevated proton leak controls metabolic phenotype of Fmr1-/y neurons. The mechanisms underlying how the proton leak control increases anabolism in Fmr1-/y neurons remains unclear. A rate-limiting step in controlling glycolysis and TCA cycle flux is the availability of nicotinamide adenine dinucleotide (NAD+), which is generated by mitochondrial complex I. An elevated proton leak will increase the ability of mitochondrial complex I to regenerate NAD+, thus increasing glycolysis and TCA cycle (Figure 1).A cardinal feature of Fragile-X is increased mRNA translation, which results in elevated protein synthesis rates. Licznerski et al. demonstrate that DEX or small interfering RNA (siRNA) directed to the c-subunit of ATP synthase were able to reduce protein synthesis Fmr1-/y neurons. By contrast, the overexpression of c-subunit in Fmr1-/y neurons increased protein synthesis. Collectively, these experiments indicate that the c-subunit-dependent proton leak is required and sufficient to increase protein synthesis rates in Fmr1-/y neurons. How proton leak controls protein synthesis remains unknown. Previous studies in Fmr1-/y mice have demonstrated hyperactivation of two pathways that control protein synthesis, the mTORC1 (mechanistic target of rapamycin complex I) and MAPK/ERK (mitogen-activated protein kinase/extracellular signal-regulated kinase) pathways (Gantois et al., 2019Gantois I. Popic J. Khoutorsky A. Sonenberg N. Metformin for Treatment of Fragile X Syndrome and Other Neurological Disorders.Annu Rev Med. 2019; 70: 167-181Crossref PubMed Scopus (36) Google Scholar). It would be of interest to know if these pathways are connected to the c-subunit-dependent proton leak. One simple explanation might be that the proton leak increases levels of glycolytic and TCA cycle metabolites that are known to hyperactivate mTORC1, leading to enhanced protein synthesis and impaired synaptic development (Figure 1).To connect the abnormal protein synthesis with Fragile-X pathophysiology, the authors turn to neuronal-stimulation-dependent rapid protein expression. With this model, excitatory stimulation of WT synaptosomes results in rapid initiation of protein synthesis that is absent in Fmr1-/y-derived synaptosomes. The phenomenon in Fmr1-/y is effectively reversed by pharmacologic closure of the proton leak. The authors are also able to demonstrate that changes in ATP synthase subunit expression are sensitive to neuronal activity and are restored to WT patterns with closure of the proton leak. Importantly, the authors use an in vivo model to investigate whether the proton leak has any impact on the neurobehavioral phenotype of Fmr1-/y mice. By injecting DEX, the authors demonstrate normalization of some behaviors (grooming, nestlet shredding, hyperactivity) without altering the behavior of WT mice (Figure 1). Going forward, an important genetic validation of the DEX experiment would be to genetically diminish the c-subunit and cross them to Fmr1-/y mice.Together, the experimental evidence provided by Licznerski and colleagues shed light on a potentially treatable pathway for Fragile-X syndrome. Applying the findings generated by Licznerski et al. to connect the proton leak and increase in metabolism to synaptic plasticity for Fragile-X syndrome opens up future research on metabolic dysregulation as a driver of neurological pathologies. Fragile-X syndrome is the most common form of inherited intellectual disability with severe, pervasive neurologic symptoms including autism, motor dysfunction, and increased risk of epilepsy. Fragile-X syndrome is caused by loss-of-function mutations in the Fragile X mental retardation (FMR1) gene located on the X chromosome. It is not fully understood how FMR1 mutations impair brain function. Previous studies have linked mitochondrial dysfunction to Fragile-X syndrome. Recently, Licznerski et al. demonstrate that proton leak within the inner mitochondrial membrane is a causal link between abnormal mitochondrial function and Fragile-X-syndrome-related neuronal phenotypes. The FMR1 gene is disrupted by expansion of a CGG triplet repeat sequence, which results in DNA hypermethylation and silencing of FMR1 when the repeats exceed 200 copies. Alternatively, in a small minority of cases, FMR1 may be absent or lack function for other reasons, but in all cases the FMR1 gene product Fragile-X Mental Retardation Protein (FMRP) is deficient. Most theories of Fragile-X pathophysiology are centered on the seminal finding that FMRP is clearly an RNA binding protein that regulates diverse components of the synapse, many of which are implicated in neuropsychiatric disease (Darnell et al., 2011Darnell J.C. Van Driesche S.J. Zhang C. Hung K.Y. Mele A. Fraser C.E. Stone E.F. Chen C. Fak J.J. Chi S.W. et al.FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism.Cell. 2011; 146: 247-261Abstract Full Text Full Text PDF PubMed Scopus (1377) Google Scholar). Mice deficient for Fmr1 develop symptomatology and histopathology consistent with human Fragile-X disease, including abnormal synapse development (Bassell and Warren, 2008Bassell G.J. Warren S.T. Fragile X syndrome: loss of local mRNA regulation alters synaptic development and function.Neuron. 2008; 60: 201-214Abstract Full Text Full Text PDF PubMed Scopus (794) Google Scholar). Studies of the Fmr1 knockout mouse (Fmr1-/y) gave rise to a central theory that rapid activity-dependent protein synthesis, which is critical for synaptic plasticity, is impaired in Fragile-X syndrome (Bear et al., 2004Bear M.F. Huber K.M. Warren S.T. The mGluR theory of fragile X mental retardation.Trends Neurosci. 2004; 27: 370-377Abstract Full Text Full Text PDF PubMed Scopus (1256) Google Scholar). As wild-type (WT) FMRP inhibits protein synthesis, in Fragile-X the unfettered expression of proteins is thought to interfere with more specific mechanisms that control synaptic development. An interesting aspect of the Fmr1-/y mice is that the impairment of synaptic maturation is associated with abnormal mitochondrial fusion (Shen et al., 2019Shen M. Wang F. Li M. Sah N. Stockton M.E. Tidei J.J. Gao Y. Korabelnikov T. Kannan S. Vevea J.D. et al.Reduced mitochondrial fusion and Huntingtin levels contribute to impaired dendritic maturation and behavioral deficits in Fmr1-mutant mice.Nat Neurosci. 2019; 22: 386-400Crossref PubMed Scopus (38) Google Scholar) and deficiencies in oxidative phosphorylation with preserved ATP production (D’Antoni et al., 2020D’Antoni S. de Bari L. Valenti D. Borro M. Bonaccorso C.M. Simmaco M. Vacca R.A. Catania M.V. Aberrant mitochondrial bioenergetics in the cerebral cortex of the Fmr1 knockout mouse model of fragile X syndrome.Biol Chem. 2020; 401: 497-503Crossref PubMed Scopus (24) Google Scholar). Furthermore, recent work demonstrated an abnormal proton leak in Fmr1-/y mitochondria when analyzing state 4 of mitochondrial respiration (Griffiths et al., 2020Griffiths K.K. Wang A. Wang L. Tracey M. Kleiner G. Quinzii C.M. Sun L. Yang G. Perez-Zoghbi J.F. Licznerski P. et al.Inefficient thermogenic mitochondrial respiration due to futile proton leak in a mouse model of fragile X syndrome.FASEB J. 2020; 34: 7404-7426Crossref PubMed Scopus (16) Google Scholar). The proton leak in Fmr1-/y mitochondria could be corrected by pharmacologic manipulations, which resulted in resolution of Fragile-X symptoms (Griffiths et al., 2020Griffiths K.K. Wang A. Wang L. Tracey M. Kleiner G. Quinzii C.M. Sun L. Yang G. Perez-Zoghbi J.F. Licznerski P. et al.Inefficient thermogenic mitochondrial respiration due to futile proton leak in a mouse model of fragile X syndrome.FASEB J. 2020; 34: 7404-7426Crossref PubMed Scopus (16) Google Scholar). Now work by Licznerski and colleagues addresses a missing, but crucial, mechanism for how FMRP loss causes the abnormal mitochondrial proton leak to impair synaptic plasticity (Licznerski et al., 2020Licznerski P. Park H.A. Rolyan H. Chen R. Mnatsakanyan N. Miranda P. Graham M. Wu J. Cruz-Reyes N. Mehta N. et al ATP Synthase c-Subunit Leak Causes Aberrant Cellular Metabolism in Fragile X Syndrome..Cell. 2020; 182: 1170-1185Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar). Using a combination of genetic and pharmacologic techniques in the Fmr1-/y mice, Licznerski and colleagues examined the proton leak within Fmr1-deficient neurons to show an abnormal metabolic phenotype that can be reversed pharmacologically. Importantly, they demonstrate both in vivo and behavioral findings from Fmr1-/y mice that validate the possibility of the proton leak as a causal link between abnormal mitochondrial function and Fragile-X-related neuronal phenotypes. In the first set of experiments, the authors find that in vitro mitochondrial membrane potential is approximately half of WT, a phenomenon potentially attributable to proton leak. Prior work by the group had shown that dexpramipexole (DEX) was able to block inner membrane leak activity by binding to ATP synthase (Alavian et al., 2015Alavian K.N. Dworetzky S.I. Bonanni L. Zhang P. Sacchetti S. Li H. Signore A.P. Smith P.J. Gribkoff V.K. Jonas E.A. The mitochondrial complex V-associated large-conductance inner membrane current is regulated by cyclosporine and dexpramipexole.Mol Pharmacol. 2015; 87: 1-8Crossref PubMed Scopus (34) Google Scholar). Using patch clamping of Fmr1-/y mitochondrial membranes, they demonstrate an abnormal conductance that DEX reduces. The findings strongly implicate ATP synthase itself as the source of a proton leak in Fmr1-/y mitochondria. By analyzing subunits of the ATP synthase, the authors conclude that Fmr1-/y mitochondria have similar levels of assembled ATP synthase compared to WT but elevated free c-subunit of ATP synthase that contributes to the increase in proton leak (Figure 1). Turning to the functional aspects of the identified inner membrane proton leak, the authors attempt to profile the metabolic phenotype of Fmr1-/y neurons as compared to WT. They observe increased flux through glycolysis concomitant with elevated lactate production in Fmr1-/y neurons compared to WT neurons. Interestingly, they also observe an increase in tricarboxylic acid (TCA) cycle flux in the Fmr1-/y neurons. A coordinate increase in glycolysis and TCA cycle is indicative of anabolism (DeBerardinis and Chandel, 2020DeBerardinis R.J. Chandel N.S. We need to talk about the Warburg effect.Nat Metab. 2020; 2: 127-129Crossref PubMed Scopus (227) Google Scholar) that is a salient feature of immature and developing neurons. The addition of DEX reduces glycolytic and TCA flux, indicating that elevated proton leak controls metabolic phenotype of Fmr1-/y neurons. The mechanisms underlying how the proton leak control increases anabolism in Fmr1-/y neurons remains unclear. A rate-limiting step in controlling glycolysis and TCA cycle flux is the availability of nicotinamide adenine dinucleotide (NAD+), which is generated by mitochondrial complex I. An elevated proton leak will increase the ability of mitochondrial complex I to regenerate NAD+, thus increasing glycolysis and TCA cycle (Figure 1). A cardinal feature of Fragile-X is increased mRNA translation, which results in elevated protein synthesis rates. Licznerski et al. demonstrate that DEX or small interfering RNA (siRNA) directed to the c-subunit of ATP synthase were able to reduce protein synthesis Fmr1-/y neurons. By contrast, the overexpression of c-subunit in Fmr1-/y neurons increased protein synthesis. Collectively, these experiments indicate that the c-subunit-dependent proton leak is required and sufficient to increase protein synthesis rates in Fmr1-/y neurons. How proton leak controls protein synthesis remains unknown. Previous studies in Fmr1-/y mice have demonstrated hyperactivation of two pathways that control protein synthesis, the mTORC1 (mechanistic target of rapamycin complex I) and MAPK/ERK (mitogen-activated protein kinase/extracellular signal-regulated kinase) pathways (Gantois et al., 2019Gantois I. Popic J. Khoutorsky A. Sonenberg N. Metformin for Treatment of Fragile X Syndrome and Other Neurological Disorders.Annu Rev Med. 2019; 70: 167-181Crossref PubMed Scopus (36) Google Scholar). It would be of interest to know if these pathways are connected to the c-subunit-dependent proton leak. One simple explanation might be that the proton leak increases levels of glycolytic and TCA cycle metabolites that are known to hyperactivate mTORC1, leading to enhanced protein synthesis and impaired synaptic development (Figure 1). To connect the abnormal protein synthesis with Fragile-X pathophysiology, the authors turn to neuronal-stimulation-dependent rapid protein expression. With this model, excitatory stimulation of WT synaptosomes results in rapid initiation of protein synthesis that is absent in Fmr1-/y-derived synaptosomes. The phenomenon in Fmr1-/y is effectively reversed by pharmacologic closure of the proton leak. The authors are also able to demonstrate that changes in ATP synthase subunit expression are sensitive to neuronal activity and are restored to WT patterns with closure of the proton leak. Importantly, the authors use an in vivo model to investigate whether the proton leak has any impact on the neurobehavioral phenotype of Fmr1-/y mice. By injecting DEX, the authors demonstrate normalization of some behaviors (grooming, nestlet shredding, hyperactivity) without altering the behavior of WT mice (Figure 1). Going forward, an important genetic validation of the DEX experiment would be to genetically diminish the c-subunit and cross them to Fmr1-/y mice. Together, the experimental evidence provided by Licznerski and colleagues shed light on a potentially treatable pathway for Fragile-X syndrome. Applying the findings generated by Licznerski et al. to connect the proton leak and increase in metabolism to synaptic plasticity for Fragile-X syndrome opens up future research on metabolic dysregulation as a driver of neurological pathologies. ATP Synthase c-Subunit Leak Causes Aberrant Cellular Metabolism in Fragile X SyndromeLicznerski et al.CellAugust 13, 2020In BriefLack of FMRP in Fragile X neurons is associated with a leak in the ATP synthase, the blockade of which normalizes cellular and behavioral disease phenotypes. Full-Text PDF Open Archive" @default.
• W3097452302 created "2020-11-09" @default.
• W3097452302 creator A5016435346 @default.
• W3097452302 creator A5046518034 @default.
• W3097452302 date "2020-11-01" @default.
• W3097452302 modified "2023-10-16" @default.
• W3097452302 title "Mitochondrial Dysfunction in Fragile-X Syndrome: Plugging the Leak May Save the Ship" @default.
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