A mutant light-chain ferritin that causes neurodegeneration has enhanced propensity toward oxidative damage

Martin A. Baraibar, Ana G. Barbeito, Barry B. Muhoberac, Ruben Vidal

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

Intracellular inclusion bodies (IBs) containing ferritin and iron are hallmarks of hereditary ferritinopathy (HF). This neurodegenerative disease is caused by mutations in the coding sequence of the ferritin light chain (FTL) gene that generate FTL polypeptides with a C-terminus that is altered in amino acid sequence and length. Previous studies of ferritin formed with p.Phe167SerfsX26 mutant FTL (Mt-FTL) subunits found disordered 4-fold pores, iron mishandling, and proaggregative behavior, as well as a general increase in cellular oxidative stress when expressed in vivo. Herein, we demonstrate that Mt-FTL is also a target of iron-catalyzed oxidative damage in vitro and in vivo. Incubation of recombinant Mt-FTL ferritin with physiological concentrations of iron and ascorbate resulted in shell structural disruption and polypeptide cleavage not seen with the wild type, as well as a 2.5-fold increase in carbonyl group formation. However, Mt-FTL shell disruption and polypeptide cleavage were completely inhibited by the addition of the radical trap 5,5-dimethyl-1- pyrroline N-oxide. These results indicate an enhanced propensity of Mt-FTL toward free radical-induced oxidative damage in vitro. We also found evidence of extensive carbonylation in IBs from a patient with HF together with isolation of a C-terminal Mt-FTL fragment, which are both indicative of oxidative ferritin damage in vivo. Our data demonstrate an enhanced propensity of mutant ferritin to undergo iron-catalyzed oxidative damage and support this as a mechanism causing disruption of ferritin structure and iron mishandling that contribute to the pathology of HF.

Original languageEnglish
Pages (from-to)1692-1697
Number of pages6
JournalFree Radical Biology and Medicine
Volume52
Issue number9
DOIs
StatePublished - May 1 2012

Fingerprint

Apoferritins
Ferritins
Iron
Inclusion Bodies
Peptides
Neurodegenerative diseases
Carbonylation
Oxidative stress
Pathology
Neurodegenerative Diseases
Free Radicals
Amino Acid Sequence
Oxidative Stress
Genes
Amino Acids
Mutation
Neuroferritinopathy

Keywords

  • Ferritin
  • Free radicals
  • Iron
  • Neurodegeneration
  • Oxidative damage

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

Cite this

A mutant light-chain ferritin that causes neurodegeneration has enhanced propensity toward oxidative damage. / Baraibar, Martin A.; Barbeito, Ana G.; Muhoberac, Barry B.; Vidal, Ruben.

In: Free Radical Biology and Medicine, Vol. 52, No. 9, 01.05.2012, p. 1692-1697.

Research output: Contribution to journalArticle

Baraibar, Martin A. ; Barbeito, Ana G. ; Muhoberac, Barry B. ; Vidal, Ruben. / A mutant light-chain ferritin that causes neurodegeneration has enhanced propensity toward oxidative damage. In: Free Radical Biology and Medicine. 2012 ; Vol. 52, No. 9. pp. 1692-1697.
@article{d3b80a7bcec84a49a76086d26beaedf8,
title = "A mutant light-chain ferritin that causes neurodegeneration has enhanced propensity toward oxidative damage",
abstract = "Intracellular inclusion bodies (IBs) containing ferritin and iron are hallmarks of hereditary ferritinopathy (HF). This neurodegenerative disease is caused by mutations in the coding sequence of the ferritin light chain (FTL) gene that generate FTL polypeptides with a C-terminus that is altered in amino acid sequence and length. Previous studies of ferritin formed with p.Phe167SerfsX26 mutant FTL (Mt-FTL) subunits found disordered 4-fold pores, iron mishandling, and proaggregative behavior, as well as a general increase in cellular oxidative stress when expressed in vivo. Herein, we demonstrate that Mt-FTL is also a target of iron-catalyzed oxidative damage in vitro and in vivo. Incubation of recombinant Mt-FTL ferritin with physiological concentrations of iron and ascorbate resulted in shell structural disruption and polypeptide cleavage not seen with the wild type, as well as a 2.5-fold increase in carbonyl group formation. However, Mt-FTL shell disruption and polypeptide cleavage were completely inhibited by the addition of the radical trap 5,5-dimethyl-1- pyrroline N-oxide. These results indicate an enhanced propensity of Mt-FTL toward free radical-induced oxidative damage in vitro. We also found evidence of extensive carbonylation in IBs from a patient with HF together with isolation of a C-terminal Mt-FTL fragment, which are both indicative of oxidative ferritin damage in vivo. Our data demonstrate an enhanced propensity of mutant ferritin to undergo iron-catalyzed oxidative damage and support this as a mechanism causing disruption of ferritin structure and iron mishandling that contribute to the pathology of HF.",
keywords = "Ferritin, Free radicals, Iron, Neurodegeneration, Oxidative damage",
author = "Baraibar, {Martin A.} and Barbeito, {Ana G.} and Muhoberac, {Barry B.} and Ruben Vidal",
year = "2012",
month = "5",
day = "1",
doi = "10.1016/j.freeradbiomed.2012.02.015",
language = "English",
volume = "52",
pages = "1692--1697",
journal = "Free Radical Biology and Medicine",
issn = "0891-5849",
publisher = "Elsevier Inc.",
number = "9",

}

TY - JOUR

T1 - A mutant light-chain ferritin that causes neurodegeneration has enhanced propensity toward oxidative damage

AU - Baraibar, Martin A.

AU - Barbeito, Ana G.

AU - Muhoberac, Barry B.

AU - Vidal, Ruben

PY - 2012/5/1

Y1 - 2012/5/1

N2 - Intracellular inclusion bodies (IBs) containing ferritin and iron are hallmarks of hereditary ferritinopathy (HF). This neurodegenerative disease is caused by mutations in the coding sequence of the ferritin light chain (FTL) gene that generate FTL polypeptides with a C-terminus that is altered in amino acid sequence and length. Previous studies of ferritin formed with p.Phe167SerfsX26 mutant FTL (Mt-FTL) subunits found disordered 4-fold pores, iron mishandling, and proaggregative behavior, as well as a general increase in cellular oxidative stress when expressed in vivo. Herein, we demonstrate that Mt-FTL is also a target of iron-catalyzed oxidative damage in vitro and in vivo. Incubation of recombinant Mt-FTL ferritin with physiological concentrations of iron and ascorbate resulted in shell structural disruption and polypeptide cleavage not seen with the wild type, as well as a 2.5-fold increase in carbonyl group formation. However, Mt-FTL shell disruption and polypeptide cleavage were completely inhibited by the addition of the radical trap 5,5-dimethyl-1- pyrroline N-oxide. These results indicate an enhanced propensity of Mt-FTL toward free radical-induced oxidative damage in vitro. We also found evidence of extensive carbonylation in IBs from a patient with HF together with isolation of a C-terminal Mt-FTL fragment, which are both indicative of oxidative ferritin damage in vivo. Our data demonstrate an enhanced propensity of mutant ferritin to undergo iron-catalyzed oxidative damage and support this as a mechanism causing disruption of ferritin structure and iron mishandling that contribute to the pathology of HF.

AB - Intracellular inclusion bodies (IBs) containing ferritin and iron are hallmarks of hereditary ferritinopathy (HF). This neurodegenerative disease is caused by mutations in the coding sequence of the ferritin light chain (FTL) gene that generate FTL polypeptides with a C-terminus that is altered in amino acid sequence and length. Previous studies of ferritin formed with p.Phe167SerfsX26 mutant FTL (Mt-FTL) subunits found disordered 4-fold pores, iron mishandling, and proaggregative behavior, as well as a general increase in cellular oxidative stress when expressed in vivo. Herein, we demonstrate that Mt-FTL is also a target of iron-catalyzed oxidative damage in vitro and in vivo. Incubation of recombinant Mt-FTL ferritin with physiological concentrations of iron and ascorbate resulted in shell structural disruption and polypeptide cleavage not seen with the wild type, as well as a 2.5-fold increase in carbonyl group formation. However, Mt-FTL shell disruption and polypeptide cleavage were completely inhibited by the addition of the radical trap 5,5-dimethyl-1- pyrroline N-oxide. These results indicate an enhanced propensity of Mt-FTL toward free radical-induced oxidative damage in vitro. We also found evidence of extensive carbonylation in IBs from a patient with HF together with isolation of a C-terminal Mt-FTL fragment, which are both indicative of oxidative ferritin damage in vivo. Our data demonstrate an enhanced propensity of mutant ferritin to undergo iron-catalyzed oxidative damage and support this as a mechanism causing disruption of ferritin structure and iron mishandling that contribute to the pathology of HF.

KW - Ferritin

KW - Free radicals

KW - Iron

KW - Neurodegeneration

KW - Oxidative damage

UR - http://www.scopus.com/inward/record.url?scp=84858971462&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84858971462&partnerID=8YFLogxK

U2 - 10.1016/j.freeradbiomed.2012.02.015

DO - 10.1016/j.freeradbiomed.2012.02.015

M3 - Article

C2 - 22348978

AN - SCOPUS:84858971462

VL - 52

SP - 1692

EP - 1697

JO - Free Radical Biology and Medicine

JF - Free Radical Biology and Medicine

SN - 0891-5849

IS - 9

ER -