Altered zinc transport disrupts mitochondrial protein processing/import in fragile X-associated tremor/ataxia syndrome

Eleonora Napoli, Catherine Ross-Inta, Sarah Wong, Alicja Omanska-Klusek, Cedrick Barrow, Christine Iwahashi, Dolores Garcia-Arocena, Danielle Sakaguchi, Elizabeth Berry-Kravis, Randi J Hagerman, Paul J Hagerman, Cecilia R Giulivi

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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 b-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.

Original languageEnglish (US)
Article numberddr211
Pages (from-to)3079-3092
Number of pages14
JournalHuman Molecular Genetics
Volume20
Issue number15
DOIs
StatePublished - Aug 2011

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Mitochondrial Proteins
Zinc
Aconitate Hydratase
Adenosine Triphosphatases
Fibroblasts
Intellectual Disability
Iron
Gait Ataxia
Friedreich Ataxia
Deferoxamine
Oxidative Phosphorylation
Pathologic Processes
Neurodegenerative Diseases
Fragile X Tremor Ataxia Syndrome
Proteins
Homeostasis
Peptide Hydrolases
Messenger RNA
frataxin
Genes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

Altered zinc transport disrupts mitochondrial protein processing/import in fragile X-associated tremor/ataxia syndrome. / Napoli, Eleonora; Ross-Inta, Catherine; Wong, Sarah; Omanska-Klusek, Alicja; Barrow, Cedrick; Iwahashi, Christine; Garcia-Arocena, Dolores; Sakaguchi, Danielle; Berry-Kravis, Elizabeth; Hagerman, Randi J; Hagerman, Paul J; Giulivi, Cecilia R.

In: Human Molecular Genetics, Vol. 20, No. 15, ddr211, 08.2011, p. 3079-3092.

Research output: Contribution to journalArticle

Napoli, E, Ross-Inta, C, Wong, S, Omanska-Klusek, A, Barrow, C, Iwahashi, C, Garcia-Arocena, D, Sakaguchi, D, Berry-Kravis, E, Hagerman, RJ, Hagerman, PJ & Giulivi, CR 2011, 'Altered zinc transport disrupts mitochondrial protein processing/import in fragile X-associated tremor/ataxia syndrome', Human Molecular Genetics, vol. 20, no. 15, ddr211, pp. 3079-3092. https://doi.org/10.1093/hmg/ddr211
Napoli, Eleonora ; Ross-Inta, Catherine ; Wong, Sarah ; Omanska-Klusek, Alicja ; Barrow, Cedrick ; Iwahashi, Christine ; Garcia-Arocena, Dolores ; Sakaguchi, Danielle ; Berry-Kravis, Elizabeth ; Hagerman, Randi J ; Hagerman, Paul J ; Giulivi, Cecilia R. / Altered zinc transport disrupts mitochondrial protein processing/import in fragile X-associated tremor/ataxia syndrome. In: Human Molecular Genetics. 2011 ; Vol. 20, No. 15. pp. 3079-3092.
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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 b-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.",
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AU - Barrow, Cedrick

AU - Iwahashi, Christine

AU - Garcia-Arocena, Dolores

AU - Sakaguchi, Danielle

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