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Updated: Feb 5, 2026
High Throughput Analysis of Liquid Droplet Impacts
Published on: March 6, 2020
Impact of
Eleonora Napoli1, Andrea Schneider2,3, Randi Hagerman2,3
1Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, Davis, CA, United States.
Abstract:
Mitochondrial dysfunction (MD) has been identified in lymphocytes, fibroblasts and brain samples from adults carrying a 55-200 CGG expansion in the fragile X mental retardation 1 (FMR1) gene (premutation; PM); however, limited data are available on the bioenergetics of pediatric carriers. Here we discuss a case report of three PM carriers: two monozygotic twins (aged 8 years) harboring an FMR1 allele with 150-180 CGG repeats, with no cognitive or intellectual issues but diagnosed with depression, mood instability and ADHD, and their mother (asymptomatic carrier with 78 CGG repeats). Fibroblasts and lymphocytes from the twins presented a generalized OXPHOS deficit, altered mitochondrial network, accumulation of depolarized mitochondria, and increased mitochondrial ROS production, outcomes distinct and more severe than the mother's ones, suggesting the involvement of modulatory effects mediated by CGG expansion, X-activation ratio, sex hormones and epigenetic factors (chronic inflammation, consequence of Lyme disease). The degree of the severity of MD appeared to segregate with the morbidity of the phenotype. The mitochondrial ROS-mediated HIF-1α stabilization was identified as a key player at contributing to the MD, pointing it as a novel target for future therapeutical intervention.
Insights
Pediatric fragile X premutation carriers show significant mitochondrial dysfunction, impacting cellular energy production and increasing oxidative stress. This mitochondrial dysfunction correlates with clinical symptoms, suggesting it as a therapeutic target.
Area of Science:
- Genetics
- Cell Biology
- Neuroscience
Background:
- Mitochondrial dysfunction (MD) is documented in adult fragile X premutation (PM) carriers.
- Limited data exist on pediatric PM carriers' bioenergetics and mitochondrial health.
Purpose of the Study:
- To investigate mitochondrial function and bioenergetics in pediatric fragile X premutation carriers.
- To explore the relationship between CGG repeat expansion, mitochondrial dysfunction, and clinical phenotype in a pediatric case.
Main Methods:
- Case report analysis of three PM carriers (two pediatric twins, one adult mother).
- Assessment of cellular bioenergetics, mitochondrial network integrity, mitochondrial reactive oxygen species (ROS) production, and HIF-1α stabilization in fibroblasts and lymphocytes.
Main Results:
- Pediatric twins exhibited generalized OXPHOS deficit, altered mitochondrial networks, and increased mitochondrial ROS, distinct from their mother.
- Mitochondrial dysfunction severity correlated with phenotypic morbidity.
- Mitochondrial ROS-mediated HIF-1α stabilization was identified as a key factor in MD.
Conclusions:
- Pediatric PM carriers can present with significant mitochondrial dysfunction.
- CGG expansion, X-activation ratio, sex hormones, and epigenetic factors may modulate MD.
- Targeting mitochondrial ROS and HIF-1α stabilization offers a potential therapeutic strategy for MD in PM carriers.
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