Defective mitochondrial disulfide relay system, altered mitochondrial morphology and function in Huntington's disease

Eleonora Napoli, Sarah Wong, Connie Hung, Catherine Ross-Inta, Prithvi Bomdica, Cecilia R Giulivi

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

A number of studies have been conducted that link mitochondrial dysfunction (MD) to Huntington's disease (HD); however, contradicting results had resulted in a lack of a clear mechanism that links expression of mutant Huntingtin protein and MD. Mouse homozygous (HM) and heterozygous (HT) mutant striatal cells with two or one allele encoding for a mutant huntingtin protein with 111 polyGln repeats showed a significant impairment of the mitochondrial disulfide relay system (MDRS). This system (consisting of two proteins, Gfer and Mia40) is involved in the mitochondrial import of Cys-rich proteins. The Gfer-to-Mia40 ratio was significantly altered in HM cells compared with controls, along with the expression of mitochondrial proteins considered substrates of the MDRS. In progenitors and differentiated neuron-like HM cells, impairment of MDRS were accompanied by deficient oxidative phosphorylation, Complex I, IV and V activities, decreased mtDNA copy number and transcripts, accumulation of mtDNA deletions and changes in mitochondrial morphology, consistent with other MDRS-deficient biological models, thus providing a framework for the energy deficits observed in this HD model. The majority (>90%) of the mitochondrial outcomes exhibited a gene-dose dependency with the expression of mutant Htt. Finally, decreases in the mtDNA copy number, along with the accumulation of mtDNA deletions, provide a mechanism for the progressive neurodegeneration observed in HD patients.

Original languageEnglish (US)
Article numberdds503
Pages (from-to)989-1004
Number of pages16
JournalHuman Molecular Genetics
Volume22
Issue number5
DOIs
StatePublished - Mar 2013

Fingerprint

Huntington Disease
Mitochondrial DNA
Disulfides
Mutant Proteins
Corpus Striatum
Biological Models
Mitochondrial Proteins
Oxidative Phosphorylation
Proteins
Alleles
Neurons
Genes
Huntingtin Protein

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

Defective mitochondrial disulfide relay system, altered mitochondrial morphology and function in Huntington's disease. / Napoli, Eleonora; Wong, Sarah; Hung, Connie; Ross-Inta, Catherine; Bomdica, Prithvi; Giulivi, Cecilia R.

In: Human Molecular Genetics, Vol. 22, No. 5, dds503, 03.2013, p. 989-1004.

Research output: Contribution to journalArticle

Napoli, Eleonora ; Wong, Sarah ; Hung, Connie ; Ross-Inta, Catherine ; Bomdica, Prithvi ; Giulivi, Cecilia R. / Defective mitochondrial disulfide relay system, altered mitochondrial morphology and function in Huntington's disease. In: Human Molecular Genetics. 2013 ; Vol. 22, No. 5. pp. 989-1004.
@article{1b086537ddf54a9fa64ad14aa27fecc6,
title = "Defective mitochondrial disulfide relay system, altered mitochondrial morphology and function in Huntington's disease",
abstract = "A number of studies have been conducted that link mitochondrial dysfunction (MD) to Huntington's disease (HD); however, contradicting results had resulted in a lack of a clear mechanism that links expression of mutant Huntingtin protein and MD. Mouse homozygous (HM) and heterozygous (HT) mutant striatal cells with two or one allele encoding for a mutant huntingtin protein with 111 polyGln repeats showed a significant impairment of the mitochondrial disulfide relay system (MDRS). This system (consisting of two proteins, Gfer and Mia40) is involved in the mitochondrial import of Cys-rich proteins. The Gfer-to-Mia40 ratio was significantly altered in HM cells compared with controls, along with the expression of mitochondrial proteins considered substrates of the MDRS. In progenitors and differentiated neuron-like HM cells, impairment of MDRS were accompanied by deficient oxidative phosphorylation, Complex I, IV and V activities, decreased mtDNA copy number and transcripts, accumulation of mtDNA deletions and changes in mitochondrial morphology, consistent with other MDRS-deficient biological models, thus providing a framework for the energy deficits observed in this HD model. The majority (>90{\%}) of the mitochondrial outcomes exhibited a gene-dose dependency with the expression of mutant Htt. Finally, decreases in the mtDNA copy number, along with the accumulation of mtDNA deletions, provide a mechanism for the progressive neurodegeneration observed in HD patients.",
author = "Eleonora Napoli and Sarah Wong and Connie Hung and Catherine Ross-Inta and Prithvi Bomdica and Giulivi, {Cecilia R}",
year = "2013",
month = "3",
doi = "10.1093/hmg/dds503",
language = "English (US)",
volume = "22",
pages = "989--1004",
journal = "Human Molecular Genetics",
issn = "0964-6906",
publisher = "Oxford University Press",
number = "5",

}

TY - JOUR

T1 - Defective mitochondrial disulfide relay system, altered mitochondrial morphology and function in Huntington's disease

AU - Napoli, Eleonora

AU - Wong, Sarah

AU - Hung, Connie

AU - Ross-Inta, Catherine

AU - Bomdica, Prithvi

AU - Giulivi, Cecilia R

PY - 2013/3

Y1 - 2013/3

N2 - A number of studies have been conducted that link mitochondrial dysfunction (MD) to Huntington's disease (HD); however, contradicting results had resulted in a lack of a clear mechanism that links expression of mutant Huntingtin protein and MD. Mouse homozygous (HM) and heterozygous (HT) mutant striatal cells with two or one allele encoding for a mutant huntingtin protein with 111 polyGln repeats showed a significant impairment of the mitochondrial disulfide relay system (MDRS). This system (consisting of two proteins, Gfer and Mia40) is involved in the mitochondrial import of Cys-rich proteins. The Gfer-to-Mia40 ratio was significantly altered in HM cells compared with controls, along with the expression of mitochondrial proteins considered substrates of the MDRS. In progenitors and differentiated neuron-like HM cells, impairment of MDRS were accompanied by deficient oxidative phosphorylation, Complex I, IV and V activities, decreased mtDNA copy number and transcripts, accumulation of mtDNA deletions and changes in mitochondrial morphology, consistent with other MDRS-deficient biological models, thus providing a framework for the energy deficits observed in this HD model. The majority (>90%) of the mitochondrial outcomes exhibited a gene-dose dependency with the expression of mutant Htt. Finally, decreases in the mtDNA copy number, along with the accumulation of mtDNA deletions, provide a mechanism for the progressive neurodegeneration observed in HD patients.

AB - A number of studies have been conducted that link mitochondrial dysfunction (MD) to Huntington's disease (HD); however, contradicting results had resulted in a lack of a clear mechanism that links expression of mutant Huntingtin protein and MD. Mouse homozygous (HM) and heterozygous (HT) mutant striatal cells with two or one allele encoding for a mutant huntingtin protein with 111 polyGln repeats showed a significant impairment of the mitochondrial disulfide relay system (MDRS). This system (consisting of two proteins, Gfer and Mia40) is involved in the mitochondrial import of Cys-rich proteins. The Gfer-to-Mia40 ratio was significantly altered in HM cells compared with controls, along with the expression of mitochondrial proteins considered substrates of the MDRS. In progenitors and differentiated neuron-like HM cells, impairment of MDRS were accompanied by deficient oxidative phosphorylation, Complex I, IV and V activities, decreased mtDNA copy number and transcripts, accumulation of mtDNA deletions and changes in mitochondrial morphology, consistent with other MDRS-deficient biological models, thus providing a framework for the energy deficits observed in this HD model. The majority (>90%) of the mitochondrial outcomes exhibited a gene-dose dependency with the expression of mutant Htt. Finally, decreases in the mtDNA copy number, along with the accumulation of mtDNA deletions, provide a mechanism for the progressive neurodegeneration observed in HD patients.

UR - http://www.scopus.com/inward/record.url?scp=84873446708&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84873446708&partnerID=8YFLogxK

U2 - 10.1093/hmg/dds503

DO - 10.1093/hmg/dds503

M3 - Article

VL - 22

SP - 989

EP - 1004

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 5

M1 - dds503

ER -