Missense mutations linked to friedreich ataxia have different but synergistic effects on mitochondrial frataxin isoforms

Hongqiao Li, Oleksandr Gakh, Douglas Y. Smith, Wasantha K. Ranatunga, Grazia Isaya

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Friedreich ataxia is an early-onset multisystemic disease linked to a variety of molecular defects in the nuclear gene FRDA. This gene normally encodes the iron-binding protein frataxin (FXN), which is critical for mitochondrial iron metabolism, global cellular iron homeostasis, and antioxidant protection. In most Friedreich ataxia patients, a large GAA-repeat expansion is present within the first intron of both FRDA alleles, that results in transcriptional silencing ultimately leading to insufficient levels of FXN protein in the mitochondrial matrix and probably other cellular compartments. The lack of FXN in turn impairs incorporation of iron into iron-sulfur cluster and heme cofactors, causing widespread enzymatic deficits and oxidative damage catalyzed by excess labile iron. In a minority of patients, a typical GAA expansion is present in only one FRDA allele, whereas a missense mutation is found in the other allele. Although it is known that the disease course for these patients can be as severe as for patients with two expanded FRDA alleles, the underlying pathophysiological mechanisms are not understood. Human cells normally contain two major mitochondrial isoforms of FXN (FXN42-210 and FXN81-210) that have different biochemical properties and functional roles. Using cell-free systems and different cellular models, we show that two of the most clinically severe FXN point mutations, I154F and W155R, have unique direct and indirect effects on the stability, biogenesis, or catalytic activity of FXN42-210 and FXN81-210 under physiological conditions. Our data indicate that frataxin point mutations have complex biochemical effects that synergistically contribute to the pathophysiology of Friedreich ataxia.

Original languageEnglish (US)
Pages (from-to)4116-4127
Number of pages12
JournalJournal of Biological Chemistry
Volume288
Issue number6
DOIs
StatePublished - Feb 8 2013

Fingerprint

Friedreich Ataxia
Missense Mutation
Protein Isoforms
Iron
Alleles
Point Mutation
Genes
Iron-Binding Proteins
Cell-Free System
Mitochondrial Proteins
Heme
Sulfur
Metabolism
Introns
frataxin
Catalyst activity
Homeostasis
Antioxidants
Cells
Defects

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Missense mutations linked to friedreich ataxia have different but synergistic effects on mitochondrial frataxin isoforms. / Li, Hongqiao; Gakh, Oleksandr; Smith, Douglas Y.; Ranatunga, Wasantha K.; Isaya, Grazia.

In: Journal of Biological Chemistry, Vol. 288, No. 6, 08.02.2013, p. 4116-4127.

Research output: Contribution to journalArticle

Li, Hongqiao ; Gakh, Oleksandr ; Smith, Douglas Y. ; Ranatunga, Wasantha K. ; Isaya, Grazia. / Missense mutations linked to friedreich ataxia have different but synergistic effects on mitochondrial frataxin isoforms. In: Journal of Biological Chemistry. 2013 ; Vol. 288, No. 6. pp. 4116-4127.
@article{91f7f1030815481eb21e3b604d37e633,
title = "Missense mutations linked to friedreich ataxia have different but synergistic effects on mitochondrial frataxin isoforms",
abstract = "Friedreich ataxia is an early-onset multisystemic disease linked to a variety of molecular defects in the nuclear gene FRDA. This gene normally encodes the iron-binding protein frataxin (FXN), which is critical for mitochondrial iron metabolism, global cellular iron homeostasis, and antioxidant protection. In most Friedreich ataxia patients, a large GAA-repeat expansion is present within the first intron of both FRDA alleles, that results in transcriptional silencing ultimately leading to insufficient levels of FXN protein in the mitochondrial matrix and probably other cellular compartments. The lack of FXN in turn impairs incorporation of iron into iron-sulfur cluster and heme cofactors, causing widespread enzymatic deficits and oxidative damage catalyzed by excess labile iron. In a minority of patients, a typical GAA expansion is present in only one FRDA allele, whereas a missense mutation is found in the other allele. Although it is known that the disease course for these patients can be as severe as for patients with two expanded FRDA alleles, the underlying pathophysiological mechanisms are not understood. Human cells normally contain two major mitochondrial isoforms of FXN (FXN42-210 and FXN81-210) that have different biochemical properties and functional roles. Using cell-free systems and different cellular models, we show that two of the most clinically severe FXN point mutations, I154F and W155R, have unique direct and indirect effects on the stability, biogenesis, or catalytic activity of FXN42-210 and FXN81-210 under physiological conditions. Our data indicate that frataxin point mutations have complex biochemical effects that synergistically contribute to the pathophysiology of Friedreich ataxia.",
author = "Hongqiao Li and Oleksandr Gakh and Smith, {Douglas Y.} and Ranatunga, {Wasantha K.} and Grazia Isaya",
year = "2013",
month = "2",
day = "8",
doi = "10.1074/jbc.M112.435263",
language = "English (US)",
volume = "288",
pages = "4116--4127",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "6",

}

TY - JOUR

T1 - Missense mutations linked to friedreich ataxia have different but synergistic effects on mitochondrial frataxin isoforms

AU - Li, Hongqiao

AU - Gakh, Oleksandr

AU - Smith, Douglas Y.

AU - Ranatunga, Wasantha K.

AU - Isaya, Grazia

PY - 2013/2/8

Y1 - 2013/2/8

N2 - Friedreich ataxia is an early-onset multisystemic disease linked to a variety of molecular defects in the nuclear gene FRDA. This gene normally encodes the iron-binding protein frataxin (FXN), which is critical for mitochondrial iron metabolism, global cellular iron homeostasis, and antioxidant protection. In most Friedreich ataxia patients, a large GAA-repeat expansion is present within the first intron of both FRDA alleles, that results in transcriptional silencing ultimately leading to insufficient levels of FXN protein in the mitochondrial matrix and probably other cellular compartments. The lack of FXN in turn impairs incorporation of iron into iron-sulfur cluster and heme cofactors, causing widespread enzymatic deficits and oxidative damage catalyzed by excess labile iron. In a minority of patients, a typical GAA expansion is present in only one FRDA allele, whereas a missense mutation is found in the other allele. Although it is known that the disease course for these patients can be as severe as for patients with two expanded FRDA alleles, the underlying pathophysiological mechanisms are not understood. Human cells normally contain two major mitochondrial isoforms of FXN (FXN42-210 and FXN81-210) that have different biochemical properties and functional roles. Using cell-free systems and different cellular models, we show that two of the most clinically severe FXN point mutations, I154F and W155R, have unique direct and indirect effects on the stability, biogenesis, or catalytic activity of FXN42-210 and FXN81-210 under physiological conditions. Our data indicate that frataxin point mutations have complex biochemical effects that synergistically contribute to the pathophysiology of Friedreich ataxia.

AB - Friedreich ataxia is an early-onset multisystemic disease linked to a variety of molecular defects in the nuclear gene FRDA. This gene normally encodes the iron-binding protein frataxin (FXN), which is critical for mitochondrial iron metabolism, global cellular iron homeostasis, and antioxidant protection. In most Friedreich ataxia patients, a large GAA-repeat expansion is present within the first intron of both FRDA alleles, that results in transcriptional silencing ultimately leading to insufficient levels of FXN protein in the mitochondrial matrix and probably other cellular compartments. The lack of FXN in turn impairs incorporation of iron into iron-sulfur cluster and heme cofactors, causing widespread enzymatic deficits and oxidative damage catalyzed by excess labile iron. In a minority of patients, a typical GAA expansion is present in only one FRDA allele, whereas a missense mutation is found in the other allele. Although it is known that the disease course for these patients can be as severe as for patients with two expanded FRDA alleles, the underlying pathophysiological mechanisms are not understood. Human cells normally contain two major mitochondrial isoforms of FXN (FXN42-210 and FXN81-210) that have different biochemical properties and functional roles. Using cell-free systems and different cellular models, we show that two of the most clinically severe FXN point mutations, I154F and W155R, have unique direct and indirect effects on the stability, biogenesis, or catalytic activity of FXN42-210 and FXN81-210 under physiological conditions. Our data indicate that frataxin point mutations have complex biochemical effects that synergistically contribute to the pathophysiology of Friedreich ataxia.

UR - http://www.scopus.com/inward/record.url?scp=84873644230&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84873644230&partnerID=8YFLogxK

U2 - 10.1074/jbc.M112.435263

DO - 10.1074/jbc.M112.435263

M3 - Article

VL - 288

SP - 4116

EP - 4127

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 6

ER -