Altered mitochondrial function in cells carrying a premutation or unmethylated full mutation of the FMR1 gene

Nobile, Veronica; Palumbo, Federica; Lanni, Stella; Ghisio, Valentina; Vitali, Alberto; Castagnola, Massimo; Marzano, Valeria; Maulucci, Giuseppe; Angelis, Claudio De; Spirito, Marco De; Pacini, Laura; D’Andrea, L.; Ragno, Rino; Stazi, Giulia; Mai, Antonello; Chiurazzi, Pietro; Genuardi, Maurizio; Neri, Giovanni; Tabolacci, Elisabetta

doi:10.1007/s00439-019-02104-7

Cited by 20 publications

(16 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In dendrites, mitochondria had a larger surface area, while mitochondria were longer in the AIS of Fmr1 KO neurons (Fig 1). This increase in mitochondrial size contrasts with previous studies reporting smaller and rounder mitochondria in animal models of FXS (Shen et al, 2019;Weisz et al, 2018), although one study using human neurons found no differences in mitochondrial morphology between patient cells and controls (Nobile et al, 2020). There are several possibilities that could account for the discrepancy in our results compared to others: 1. the increased size may represent mitochondrial "swelling", which is a phenotype typically associated with dysfunctional mitochondria.…”

Section: Resultscontrasting

confidence: 99%

Mitochondrial Structure and Polarity in Dendrites and the Axon Initial Segment are Regulated by Homeostatic Plasticity and Dysregulated in Fragile X Syndrome

Bülow

Wenner

Faundez

et al. 2021

Preprint

View full text Add to dashboard Cite

Mitochondrial dysfunction has long been overlooked in neurodevelopmental disorders, but recent studies have provided new links to genetic forms of autism, including Rett syndrome and Fragile X Syndrome (FXS). In parallel, recent studies have uncovered important basic functions of mitochondria to power protein synthesis, synaptic plasticity and neuronal maturation. The mitochondrion also responds to neuronal activity by altering its morphology and function, and this plasticity of the mitochondrion appear important for proper neuronal plasticity. Previous research has reported disease induced changes in mitochondrial morphology and function, but it remains unknown how such abnormalities affect the ability of mitochondria to express activity dependent plasticity. This study addresses this gap in knowledge using a mouse model of FXS. We previously reported abnormalities in one type of homeostatic plasticity, called homeostatic intrinsic plasticity, which is known to involve structural changes in the axon initial segment (AIS). Another form of homeostatic plasticity, called synaptic scaling, which involves postsynaptic changes in dendrites, is also impaired in FXS. It remains unknown if or how homeostatic plasticity affects mitochondria in axons and/or dendrites and whether impairments occur in neurodevelopmental disorders. Here, we test the hypothesis that mitochondria are structurally and functionally modified in a compartment specific manner during homeostatic plasticity in cortical neurons from wild type mice, and that this plasticity-induced regulation is altered in Fmr1 KO neurons, as a model of FXS. We uncovered dendritic specific regulation of mitochondrial surface area, whereas AIS mitochondria show changes in polarity; both responses are lost in Fmr1 KO. Taken together our results demonstrate impairments in mitochondrial plasticity in FXS, which has not previously been reported. These results suggest that mitochondrial dysregulation in FXS contributes to abnormal neuronal plasticity, with broader implications to other neurodevelopmental disorders and therapeutic strategies.

show abstract

Section: Resultscontrasting

confidence: 99%

Mitochondrial Structure and Polarity in Dendrites and the Axon Initial Segment are Regulated by Homeostatic Plasticity and Dysregulated in Fragile X Syndrome

Bülow

Wenner

Faundez

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…Mitochondrial dysfunction (MD) is at the center of many disorders, especially those affecting neurological systems, due to the heavy reliance of neurons on mitochondrial ATP [ 9 ]. In this context, our team reported for the first time MD in bio-samples from pediatric and adult carriers, with and without FXTAS [ 10 , 11 ], some of which were later replicated and confirmed by others [ 12 , 13 , 14 ]. More importantly, the MD observed in PBMCs was associated with CNS deficits (i.e., lower executive function and IQ, increased anxiety, fatigue, and attention deficit hyperactivity disorder [ 15 ]), and evidenced before the overt accumulation of nuclear inclusions—a hallmark of FXTAS [ 16 ]—or behavioral deficits [ 10 ].…”

Section: Introductionmentioning

confidence: 79%

Deficits in Prenatal Serine Biosynthesis Underlie the Mitochondrial Dysfunction Associated with the Autism-Linked FMR1 Gene

Nolin

Napoli

Flores

et al. 2021

IJMS

View full text Add to dashboard Cite

Fifty-five to two hundred CGG repeats (called a premutation, or PM) in the 5′-UTR of the FMR1 gene are generally unstable, often expanding to a full mutation (>200) in one generation through maternal inheritance, leading to fragile X syndrome, a condition associated with autism and other intellectual disabilities. To uncover the early mechanisms of pathogenesis, we performed metabolomics and proteomics on amniotic fluids from PM carriers, pregnant with male fetuses, who had undergone amniocentesis for fragile X prenatal diagnosis. The prenatal metabolic footprint identified mitochondrial deficits, which were further validated by using internal and external cohorts. Deficits in the anaplerosis of the Krebs cycle were noted at the level of serine biosynthesis, which was confirmed by rescuing the mitochondrial dysfunction in the carriers’ umbilical cord fibroblasts using alpha-ketoglutarate precursors. Maternal administration of serine and its precursors has the potential to decrease the risk of developing energy shortages associated with mitochondrial dysfunction and linked comorbidities.

show abstract

“…Diverse metabolic alterations have been found in FMR1 premutation carriers, including perturbations in the metabolism of carbohydrates, amino acids and derivatives, biogenic amines, fatty acids, structural lipids, and nucleotide. Of note, many of those metabolic alterations can be attributed to mitochondrial dysfunction, such as decreased OXPHOS capacity, changed mitochondrial proteins and altered mitochondrial architecture, which are caused by RNA gain-of function toxicity and RAN translation (Hukema et al, 2014;Alvarez-Mora et al, 2017;Drozd et al, 2019;Gohel et al, 2019;Nobile et al, 2020). As the most downstream of FMR1 premutation pathogenesis, the metabolic alterations discussed in this review could provide resources in the search for biomarkers and promising therapeutic targets for FMR1 premutation carriers.…”

Section: Discussionmentioning

confidence: 98%

Metabolic Alterations in FMR1 Premutation Carriers

Cao

Peng

Kong

et al. 2020

Front. Mol. Biosci.

View full text Add to dashboard Cite

FMR1 gene premutation carriers are at risk of developing Fragile X-associated tremor/ataxia syndrome (FXTAS) and Fragile X-associated primary ovarian insufficiency (FXPOI) in adulthood. Currently the development of biomarkers and effective treatments in FMR1 premutations is still in its infancy. Recent metabolic studies have shown novel findings in asymptomatic FMR1 premutation carriers and FXTAS, which provide promising insight through identification of potential biomarkers and therapeutic pathways. Here we review the latest advancements of the metabolic alterations found in asymptomatic FMR1 premutation carriers and FXTAS, along with our perspective for future studies in this emerging field.

show abstract

Altered mitochondrial function in cells carrying a premutation or unmethylated full mutation of the FMR1 gene

Cited by 20 publications

References 51 publications

Mitochondrial Structure and Polarity in Dendrites and the Axon Initial Segment are Regulated by Homeostatic Plasticity and Dysregulated in Fragile X Syndrome

Mitochondrial Structure and Polarity in Dendrites and the Axon Initial Segment are Regulated by Homeostatic Plasticity and Dysregulated in Fragile X Syndrome

Deficits in Prenatal Serine Biosynthesis Underlie the Mitochondrial Dysfunction Associated with the Autism-Linked FMR1 Gene

Metabolic Alterations in FMR1 Premutation Carriers

Contact Info

Product

Resources

About