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 journalArticlepeer-review

55 Scopus citations


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
Issue number5
StatePublished - Mar 2013

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology


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