Huntington’s Disease and Mitochondrial DNA Deletions: Event or Regular Mechanism for Mutant Huntingtin Protein and CAG Repeats Expansion?!

Abstract

The mitochondrial DNA (mtDNA) may play an essential role in the pathogenesis of the respiratory chain complex activities in neurodegenerative disorders such as Huntington's disease (HD). Research studies were conducted to determine the possible levels of mitochondrial defect (deletion) in HD patients and consideration of interaction between the expanded Huntingtin gene as a nuclear gene and mitochondria as a cytoplasmic organelle. To determine mtDNA damage, we investigated deletions based in four areas of mitochondrial DNA, in a group of 60 Iranian patients clinically diagnosed with HD and 70 healthy controls. A total of 41 patients out of 60 had CAG expansion (group A). About 19 patients did not show expansion but had the clinical symptoms of HD (group B). MtDNA deletions were classified into four groups according to size; 9 kb, 7.5 kb, 7 kb, and 5 kb. We found one of the four-mtDNA deletions in at least 90% of samples. Multiple deletions have also been observed in 63% of HD patients. None of the normal control (group C) showed mtDNA deletions. The sizes or locations of the deletions did not show a clear correlation with expanded CAG repeat and age in our samples. The study presented evidence that HD patients had higher frequencies of mtDNA deletions in lymphocytes in comparison to the controls. It is thus proposed that CAG repeats instability and mutant Htt are causative factor in mtDNA damage.

Increased mitochondrial fission and neuronal dysfunction in Huntington's disease: implications for molecular inhibitors of excessive mitochondrial fission

“…Recent research has revealed multiple alterations in mitochondria, in HD progression and pathogenesis, including: (i) reduced enzymatic activity in several components of oxidative phosphorylation, including complexes II, III and IV of the electron transport chain, in HD postmortem brains and HD mouse models [22–24], suggesting that mitochondria are involved in HD pathogenesis; (ii) low mitochondrial ATP and decreased mitochondrial ADP uptake in HD knock-in striatal cells and lymphoblasts from patients with HD, revealing expanded polyglutamine repeats [25]; (iii) defective calcium-induced mitochondrial permeability in HD cell lines and HD mice (reviewed in [26]); (iv) mHtt-induced defective mitochondrial trafficking in HD primary neurons [15,17,18,27]; (v) age-dependent mitochondrial (mt)DNA damage and mtDNA deletions in HD-affected neurons [28,29]; and (vi) biochemical, confocal and electron microscopy studies revealed structurally damaged mitochondria with broken cristae, and small and round mitochondria in HD-affected neurons [18–21] (Figure 1). …”

Mitochondrial <i>tRNALeu/Lys</i> and <i>ATPase 6/8</i> Gene Variations in Spinocerebellar Ataxias

“…No mtDNA deletions have been found in SCA patients in this study. We have previously shown high frequencies of mtDNA deletions in HD and lower levels in Friedreich's ataxia [24,41] . These findings point to the existence of a complicated mechanism that directly corresponds to the type of protein involved and the related mechanism.…”

Investigation of tRNALeu/Lys and ATPase 6 Genes Mutations in Huntington’s Disease

“…Involvement of nuclei and mitochondria in HD pathophysiology has been suggested (Sawa et al 1999). Banoei et al (2007) showed that huntington patients had higher mtDNA deletions than normal controls due to the presence of CAG repeats expansion (Banoei et al 2007). Furthermore, HD patients showed increased oxidative stress, together with higher amounts of deleted mtDNA and total mtDNA in peripheral leukocytes.…”