title: Altered zinc transport disrupts mitochondrial protein processing/import in fragile X-associated tremor/ataxia syndrome.
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.
authors.affiliation: Department of Molecular Biosciences, School of Veterinary Medicine, School of Medicine, University of California Davis, Davis, CA 95616, USA.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Napoli
authors.forename: Catherine
authors.initials: C
authors.lastname: Ross-Inta
authors.forename: Sarah
authors.initials: S
authors.lastname: Wong
authors.forename: Alicja
authors.initials: A
authors.lastname: Omanska-Klusek
authors.forename: Cedrick
authors.initials: C
authors.lastname: Barrow
authors.forename: Christine
authors.initials: C
authors.lastname: Iwahashi
authors.forename: Dolores
authors.initials: D
authors.lastname: Garcia-Arocena
authors.forename: Danielle
authors.initials: D
authors.lastname: Sakaguchi
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Berry-Kravis
authors.forename: Randi
authors.initials: R
authors.lastname: Hagerman
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Hagerman
authors.forename: Cecilia
authors.initials: C
authors.lastname: Giulivi
mesh_terms: D000368:Aged; D015153:Blotting, Western; D002478:Cells, Cultured; D004272:DNA, Mitochondrial / Q000235:genetics; D005260:Female; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics / Q000378:metabolism; D005600:Fragile X Syndrome / Q000235:genetics / Q000378:metabolism*; D018628:Gene Dosage / Q000235:genetics; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D066298:In Vitro Techniques; D017136:Ion Transport / Q000235:genetics / Q000502:physiology*; D008297:Male; D024101:Mitochondrial Proteins / Q000235:genetics* / Q000378:metabolism*; D015032:Zinc / Q000378:metabolism*
chemical_list: D004272:DNA, Mitochondrial; D051860:Fragile X Messenger Ribonucleoprotein 1; D006861:Hydrogen Peroxide; D024101:Mitochondrial Proteins; D015032:Zinc; C497683:FMR1 protein, human