Region-specific analysis of mitochondrial DNA deletions in neurodegenerative disorders in humans

Mawrin, Christian; Kirches, Elmar; Krause, Guido; Schneider‐Stock, Regine; Bogerts, Bernhard; Vorwerk, Christian K.; Dietzmann, Knut

doi:10.1016/j.neulet.2003.11.073

Cited by 23 publications

(20 citation statements)

References 15 publications

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“…The nature of mutations was apparently somatic (not inherited), because individual neurons contained unique types of deleted mtDNA. Although earlier studies were unable to demonstrate the correlation between the accumulation of deleted mtDNA and AD by analyzing human cortical tissues [10,11], there could be other 'regional hotspots' where deleted mtDNA preferentially accumulates and contributes to neuronal death in AD. It remains to be determined whether the COX deficiency correlates to oxidative stress in individual brain cells in any of these conditions.…”

Section: Mitochondrial Dna Mutations and Oxidative Stress In The Aginmentioning

confidence: 91%

“…Although this model is extremely attractive, the relatively specific impairment of complex IV activity found in AD brains and platelets is not easily explainable from the stochastic accumulation of somatic mtDNA mutations. Furthermore, the evidence supporting the correlation between mtDNA mutations and AD is lacking [11,64,65].…”

Section: Origins Of Complex IV Defects In Admentioning

confidence: 99%

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The mitochondrial impairment, oxidative stress and neurodegeneration connection: reality or just an attractive hypothesis?

Fukui

Moraes

2008

Trends in Neurosciences

221

146

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Aging is the most important risk factor for common neurodegenerative disorders such as Parkinson's and Alzheimer's diseases. Aging in the central nervous system has been associated with elevated mutation load in mitochondrial DNA, defects in mitochondrial respiration and increased oxidative damage. These observations support a 'vicious cycle' theory which states that there is a feedback mechanism connecting these events in aging and age-associated neurodegeneration. Despite being an extremely attractive hypothesis, the bulk of the evidence supporting the mitochondrial vicious cycle model comes from pharmacological experiments in which the modes of mitochondrial enzyme inhibition are far from those observed in real life. Furthermore, recent in vivo evidence does not support this model. In this review, we focus on the relationship among the components of the putative vicious cycle, with particular emphasis on the role of mitochondrial defects on oxidative stress. Mitochondrial respiratory chain and reactive oxygen species productionMitochondria, being the key players in ATP production and diverse cell signaling events, are essential organelles for the survival of eukaryotic cells. Unlike all other organelles in animals, the mitochondria have their own genome (mitochondrial DNA; mtDNA) that encodes components of the oxidative phosphorylation (OXPHOS) system. The mitochondrial OXPHOS machinery is composed of five multisubunit complexes (complex I-V). From Krebs cycle intermediates (NADH and FADH 2 ), electrons feed into complex I or II, and are transferred to complex III, then to complex IV, and finally to O 2 . The redox energy released during the electron transfer process in complexes I, III and IV is utilized to actively pump out H + from the mitochondrial matrix to the intermembrane space, generating the electrochemical gradient of H + across the inner membrane which is ultimately utilized by complex V to produce ATP [1].This elegant system for energy production, however, is not perfect. A small portion (up to 2%) of electrons passing through the electron transport chain, mostly at complex I and complex III, react with molecular oxygen and yield superoxide anion, which can be converted into other reactive oxygen species (ROS) such as hydrogen peroxide and the highly reactive hydroxyl radical through enzymatic and nonenzymatic reactions [2]. Cells are endowed with robust endogenous antioxidant systems to counteract excessive ROS. It is believed that ROS, in particular hydrogen peroxide, have physiological roles as signaling molecules [3,4]. However,

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Section: Mitochondrial Dna Mutations and Oxidative Stress In The Aginmentioning

confidence: 91%

Section: Origins Of Complex IV Defects In Admentioning

confidence: 99%

The mitochondrial impairment, oxidative stress and neurodegeneration connection: reality or just an attractive hypothesis?

Fukui

Moraes

2008

Trends in Neurosciences

221

146

View full text Add to dashboard Cite

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“…Could the increased rate be a direct consequence of the expanded trinucleotide repeat of the HD gene, or could it arise indirectly? However, regarding the fact that mtDNA deletions increase with normal aging, the evaluation of the exact level of such mutations is critical to evaluate the possible contribution to pathological cell death which occurs in neurodegenerative disorders, especially with regard to the regional distribution (Mawrin et al 2004). Houshmand et al (2006) showed that FA patients had higher mtDNA deletion than normal controls due to iron accumulation (Houshmand et al 2006).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2007

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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.

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“…This trend has not been replicated in all studies [158]. Also mtDNA deletions seem to play a role in PD pathogenesis [34, 159]. Substantia nigra has the highest frequency of mtDNA deletions among all tissues, possibly due to the pro-oxidative dopamine metabolism mentioned earlier [34].…”

Section: Mitochondrial Haplogroups and Pd Riskmentioning

confidence: 97%

The Impact of Mitochondrial DNA and Nuclear Genes Related to Mitochondrial Functioning on the Risk of Parkinson’s Disease

Gawęda-Walerych

Żekanowski

2014

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Mitochondrial dysfunction and oxidative stress are the major factors implicated in Parkinson’s disease (PD) pathogenesis. The maintenance of healthy mitochondria is a very complex process coordinated bi-genomically. Here, we review association studies on mitochondrial haplogroups and subhaplogroups, discussing the underlying molecular mechanisms. We also focus on variation in the nuclear genes (NDUFV2, PGC-1alpha, HSPA9, LRPPRC, MTIF3, POLG1, and TFAM encoding NADH dehydrogenase (ubiquinone) flavoprotein 2, peroxisome proliferator-activated receptor gamma coactivator 1-alpha, mortalin, leucine-rich pentatricopeptide repeat containing protein, translation initiation factor 3, mitochondrial DNA polymerase gamma, and mitochondrial transcription factor A, respectively) primarily linked to regulation of mitochondrial functioning that recently have been associated with PD risk. Possible interactions between mitochondrial and nuclear genetic variants and related proteins are discussed.

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Region-specific analysis of mitochondrial DNA deletions in neurodegenerative disorders in humans

Cited by 23 publications

References 15 publications

The mitochondrial impairment, oxidative stress and neurodegeneration connection: reality or just an attractive hypothesis?

The mitochondrial impairment, oxidative stress and neurodegeneration connection: reality or just an attractive hypothesis?

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

The Impact of Mitochondrial DNA and Nuclear Genes Related to Mitochondrial Functioning on the Risk of Parkinson’s Disease

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