Loss of Drosophila FMRP leads to alterations in energy metabolism and mitochondrial function

Weisz, Eliana D; Towheed, Atif; Monyak, Rachel E.; Toth, Meridith S; Wallace, Douglas C.; Jongens, Thomas A.

doi:10.1093/hmg/ddx387

Cited by 42 publications

(51 citation statements)

References 63 publications

(78 reference statements)

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“…The idea of altered mitochondrial function in per 01 flies is supported by the finding of decreased AC levels as well as altered mitochondrial function in dfrm1 flies, a Drosophila model for fragile-X syndrome [70]. In line with our findings, decreased AC levels in dmfr1 flies are accompanied by decreased TAG and DAG levels, altered circadian rhythms, hypersensitivity to starvation, and wildtype-like protein content and body weight.…”

Section: Several Lines Of Evidence Point Towards Altered Mitochondriasupporting

confidence: 89%

Loss of function in the Drosophila clock gene period results in altered intermediary lipid metabolism and increased susceptibility to starvation

Schäbler

Amatobi

Horn

et al. 2020

Cell. Mol. Life Sci.

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The fruit fly Drosophila is a prime model in circadian research, but still little is known about its circadian regulation of metabolism. Daily rhythmicity in levels of several metabolites has been found, but knowledge about hydrophobic metabolites is limited. We here compared metabolite levels including lipids between period 01 (per 01) clock mutants and CantonS wildtype (WT CS) flies in an isogenic and non-isogenic background using LC-MS. In the non-isogenic background, metabolites with differing levels comprised essential amino acids, kynurenines, pterinates, glycero(phospho)lipids, and fatty acid esters. Notably, detectable diacylglycerols (DAG) and acylcarnitines (AC), involved in lipid metabolism, showed lower levels in per 01 mutants. Most of these differences disappeared in the isogenic background, yet the level differences for AC as well as DAG were consistent for fly bodies. AC levels were dependent on the time of day in WT CS in phase with food consumption under LD conditions, while DAGs showed weak daily oscillations. Two short-chain ACs continued to cycle even in constant darkness. per 01 mutants in LD showed no or very weak diel AC oscillations out of phase with feeding activity. The low levels of DAGs and ACs in per 01 did not correlate with lower total food consumption, body mass or weight. Clock mutant flies showed higher sensitivity to starvation independent of their background-dependent activity level. Our results suggest that neither feeding, energy storage nor mobilisation is significantly affected in per 01 mutants, but point towards impaired mitochondrial activity, supported by upregulation of the mitochondrial stress marker 4EBP in the clock mutants.

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Section: Several Lines Of Evidence Point Towards Altered Mitochondriasupporting

confidence: 89%

Loss of function in the Drosophila clock gene period results in altered intermediary lipid metabolism and increased susceptibility to starvation

Schäbler

Amatobi

Horn

et al. 2020

Cell. Mol. Life Sci.

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“…Although the slower Fmr1 KO mitochondria oxygen consumption rates we observed using a Clark‐type electrode were in accordance with a recently published report, we rejected the interpretation that decreased the respiration simply represented the impaired electron transport 13 . This is because such an inference contradicts prior findings from two different FXS models and would be in conflict with our data suggesting uncoupled respiration in Fmr1 mutant mice 11,12 . Because accurate and precise interpretation of changes in rates of oxygen consumption requires parallel measurement of mitochondrial membrane potential, use of in‐depth quantitative measures, such as modular kinetics, is often necessary to provide a more complete assessment of the functional state of mitochondria and permit identification of exact mechanisms of mitochondrial dysfunction 42 …”

Section: Resultssupporting

confidence: 50%

“…Taken at face value, these findings seemed to suggest defective, but coupled, oxidative phosphorylation in Fmr1 mutant mitochondria. However, such an interpretation contradicts observations from Drosophila lacking FMRP and Fmr1/Fxr2 double KO mice, making this simple conclusion unlikely 11,12 . Importantly, without parallel measurement of mitochondrial membrane potential, precise, and unambiguous interpretation of changes in rates of oxygen consumption is impossible 42 …”

Section: Resultsmentioning

confidence: 99%

“…Defects in the neuroenergetic capacity are known to cause a variety of neurodevelopmental disorders 9,10 . Prior work described alterations in metabolism in Drosophila lacking FMRP and in mice with mutations of both Fmr1 and its paralog, Fxr2 11,12 . Specifically, FXS mutants demonstrated increased electron transport chain (ETC) capacity and oxygen consumption 11,12 .…”

Section: Introductionmentioning

confidence: 99%

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Inefficient thermogenic mitochondrial respiration due to futile proton leak in a mouse model of fragile X syndrome

Griffiths

Wang

et al. 2020

FASEB j.

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Fragile X syndrome (FXS) is the leading known inherited intellectual disability and the most common genetic cause of autism. The full mutation results in transcriptional silencing of the Fmr1 gene and loss of fragile X mental retardation protein (FMRP) expression. Defects in neuroenergetic capacity are known to cause a variety of neurodevelopmental disorders. Thus, we explored the integrity of forebrain mitochondria in Fmr1 knockout mice during the peak of synaptogenesis. We found inefficient thermogenic respiration due to futile proton leak in Fmr1 KO mitochondria caused by coenzyme Q (CoQ) deficiency and an open cyclosporine‐sensitive channel. Repletion of mitochondrial CoQ within the Fmr1 KO forebrain closed the channel, blocked the pathological proton leak, restored rates of protein synthesis during synaptogenesis, and normalized the key phenotypic features later in life. The findings demonstrate that FMRP deficiency results in inefficient oxidative phosphorylation during the neurodevelopment and suggest that dysfunctional mitochondria may contribute to the FXS phenotype.

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“…In dfmr1 -KO Drosophila , the loss of FMRP was shown to elevate insulin signaling in the brain and intestine, inducing developmental defects in those organs [14], [15], [16]. Another study in the Drosophila model of FXS, highlighted reduced whole-body carbohydrate and lipid stores, hypersensitivity to starvation, and altered mitochondrial functions [17]. Although no overt metabolic alterations was reported in the first generation FXS mouse model ( Fmr1- KO1) [9], the Fmr1/Fxr2 double KO mouse displayed increased glucose tolerance and insulin sensitivity, reduced adiposity, and reduced circulating glucose [18].…”

Section: Introductionmentioning

confidence: 99%

The translational regulator FMRP controls lipid and glucose metabolism in mice and humans

Leboucher

Pisani

Martinez‐Gili

et al. 2019

Molecular Metabolism

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Objectives The Fragile X Mental Retardation Protein (FMRP) is a widely expressed RNA-binding protein involved in translation regulation. Since the absence of FMRP leads to Fragile X Syndrome (FXS) and autism, FMRP has been extensively studied in brain. The functions of FMRP in peripheral organs and on metabolic homeostasis remain elusive; therefore, we sought to investigate the systemic consequences of its absence. Methods Using metabolomics, in vivo metabolic phenotyping of the Fmr1- KO FXS mouse model and in vitro approaches, we show that the absence of FMRP induced a metabolic shift towards enhanced glucose tolerance and insulin sensitivity, reduced adiposity, and increased β-adrenergic-driven lipolysis and lipid utilization. Results Combining proteomics and cellular assays, we highlight that FMRP loss increased hepatic protein synthesis and impacted pathways notably linked to lipid metabolism. Mapping metabolomic and proteomic phenotypes onto a signaling and metabolic network, we predicted that the coordinated metabolic response to FMRP loss was mediated by dysregulation in the abundances of specific hepatic proteins. We experimentally validated these predictions, demonstrating that the translational regulator FMRP associates with a subset of mRNAs involved in lipid metabolism. Finally, we highlight that FXS patients mirror metabolic variations observed in Fmr1- KO mice with reduced circulating glucose and insulin and increased free fatty acids. Conclusions Loss of FMRP results in a widespread coordinated systemic response that notably involves upregulation of protein translation in the liver, increased utilization of lipids, and significant changes in metabolic homeostasis. Our study unravels metabolic phenotypes in FXS and further supports the importance of translational regulation in the homeostatic control of systemic metabolism.

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Loss of Drosophila FMRP leads to alterations in energy metabolism and mitochondrial function

Cited by 42 publications

References 63 publications

Loss of function in the Drosophila clock gene period results in altered intermediary lipid metabolism and increased susceptibility to starvation

Loss of function in the Drosophila clock gene period results in altered intermediary lipid metabolism and increased susceptibility to starvation

Inefficient thermogenic mitochondrial respiration due to futile proton leak in a mouse model of fragile X syndrome

The translational regulator FMRP controls lipid and glucose metabolism in mice and humans

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