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Altered zinc transport disrupts mitochondrial protein processing/import in fragile X-associated tremor/ataxia
Eleonora Napoli1, Catherine Ross-Inta, Sarah Wong
1Department of Molecular Biosciences, School of Veterinary Medicine, School of Medicine, University of California Davis, Davis, CA 95616, USA.
Abstract:
Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder that affects individuals who are carriers of small CGG premutation expansions in the fragile X mental retardation 1 (FMR1) gene. Mitochondrial dysfunction was observed as an incipient pathological process occurring in individuals who do not display overt features of FXTAS (1). Fibroblasts from premutation carriers had lower oxidative phosphorylation capacity (35% of controls) and Complex IV activity (45%), and higher precursor-to-mature ratios (P:M) of nDNA-encoded mitochondrial proteins (3.1-fold). However, fibroblasts from carriers with FXTAS symptoms presented higher FMR1 mRNA expression (3-fold) and lower Complex V (38%) and aconitase activities (43%). Higher P:M of ATPase β-subunit (ATPB) and frataxin were also observed in cortex from patients that died with FXTAS symptoms. Biochemical findings observed in FXTAS cells (lower mature frataxin, lower Complex IV and aconitase activities) along with common phenotypic traits shared by Friedreich's ataxia and FXTAS carriers (e.g. gait ataxia, loss of coordination) are consistent with a defective iron homeostasis in both diseases. Higher P:M, and lower ZnT6 and mature frataxin protein expression suggested defective zinc and iron metabolism arising from altered ZnT protein expression, which in turn impairs the activity of mitochondrial Zn-dependent proteases, critical for the import and processing of cytosolic precursors, such as frataxin. In support of this hypothesis, Zn-treated fibroblasts showed a significant recovery of ATPB P:M, ATPase activity and doubling time, whereas Zn and desferrioxamine extended these recoveries and rescued Complex IV activity.
Insights
Fragile X-associated tremor/ataxia syndrome (FXTAS) involves mitochondrial dysfunction and impaired iron and zinc metabolism. Zinc and desferrioxamine treatments show promise in restoring cellular functions in affected cells.
Area of Science:
- Neurogenetics
- Mitochondrial Biology
- Metabolic Disorders
Background:
- Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder linked to FMR1 gene premutations.
- Mitochondrial dysfunction is an early pathological sign in FXTAS carriers, even before overt symptoms appear.
- Previous studies noted reduced oxidative phosphorylation and Complex IV activity in fibroblasts from premutation carriers.
Purpose of the Study:
- To investigate the biochemical basis of mitochondrial dysfunction in FXTAS.
- To explore the role of iron and zinc metabolism in FXTAS pathogenesis.
- To assess the therapeutic potential of zinc and iron chelators in FXTAS models.
Main Methods:
- Analysis of fibroblast and cortical tissue from FXTAS carriers and controls.
- Measurement of mitochondrial oxidative phosphorylation, enzyme activities (Complex IV, V, aconitase), and protein precursor-to-mature ratios.
- Assessment of FMR1 mRNA expression.
- In vitro treatment of fibroblasts with zinc and desferrioxamine.
Main Results:
- FXTAS fibroblasts showed impaired Complex V and aconitase activity, with higher FMR1 mRNA expression.
- Elevated precursor-to-mature protein ratios (ATPB, frataxin) were observed in FXTAS cells and tissues.
- Defective iron and zinc metabolism, linked to altered ZnT protein expression, was implicated.
- Zinc and desferrioxamine treatments partially or fully restored cellular ATPB ratios, ATPase activity, and Complex IV activity.
Conclusions:
- FXTAS is associated with mitochondrial dysfunction and defective iron and zinc metabolism, potentially impacting iron homeostasis.
- Altered ZnT expression may impair mitochondrial Zn-dependent proteases, affecting precursor protein processing.
- Zinc and desferrioxamine show potential as therapeutic agents for FXTAS by improving mitochondrial function and metabolism.
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