Somatic mitochondrial DNA mutations in cortex and substantia nigra in aging and Parkinson’s disease

Simon, David K.; Lin, Michael; Zheng, Leiya; Liu, Guangjun; Ahn, Colette; Kim, Lauren M.; Mauck, William M.; Twu, Florence; Beal, M. Flint; Johns, Donald R.

doi:10.1016/s0197-4580(03)00037-x

Cited by 103 publications

(83 citation statements)

References 61 publications

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“…One drawback of this study, however, is that sequencing analysis might miss heteroplasmic mtDNA species that could be concentrated in disease-relevant cells. A more recent study employed a cloning-based sequence analysis to study the mutation load in the gene encoding ND4 in the cerebral cortex and substantia nigra of PD patients [38]. Although this study revealed a clear age-dependent increase in point mutations in control subjects, there was no significant difference in mutation load between PD and control groups.…”

Section: Origins Of Complex I Defects In Pdmentioning

confidence: 74%

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: Origins Of Complex I Defects In Pdmentioning

confidence: 74%

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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“…Deletion accumulation in PD subjects exceeds that of non-PD subjects (8,63). Point mutation burden is comparable between groups, although certain point mutations seem to be found only in PD subjects (95,121,125). It could be argued these findings imply a role for somatic mtDNA mutation in PD, but this is a somewhat complicated subject.…”

Section: Are Specific Mtdna Signatures Typical Of Pd?mentioning

confidence: 93%

“…By the mid1990s, low abundance mtDNA heteroplasmies had not been shown to exist, but this was mostly due to the fact that low abundance heteroplasmies were not detected by the routine dideoxynucleotide sequencing protocols used at the time (52). Of course, since then many of the key technical limitations responsible for this have been resolved, and it has been clearly demonstrated that low abundance heteroplasmies not only exist but are in fact commonplace (17,23,69,80,121,125).…”

Section: Swerdlowmentioning

confidence: 99%

“…In these studies methodologic approaches and in some cases interpretations have varied. These studies have generally concluded that low abundance heteroplasmic point mutations are common in the brains of aging individuals, and between PD and control subjects point mutation burdens are equivalent (4,95,121,125). In terms of mutation patterns or localizations, some have found no differences between PD and control subjects (4,121), whereas others have claimed characteristic mtDNA signatures that distinguish PD subject brains from those of control subjects.…”

Section: Are Specific Mtdna Signatures Typical Of Pd?mentioning

confidence: 99%

“…These studies have generally concluded that low abundance heteroplasmic point mutations are common in the brains of aging individuals, and between PD and control subjects point mutation burdens are equivalent (4,95,121,125). In terms of mutation patterns or localizations, some have found no differences between PD and control subjects (4,121), whereas others have claimed characteristic mtDNA signatures that distinguish PD subject brains from those of control subjects. For example, Smigrodzki et al and Parker et al have reported low-abundance heteroplasmic mutations in a defined region of the ND5 gene are found in most PD subject brains but rarely in the brains of persons who died without PD (95,125).…”

Section: Are Specific Mtdna Signatures Typical Of Pd?mentioning

confidence: 99%

See 2 more Smart Citations

Does Mitochondrial DNA Play a Role in Parkinson's Disease? A Review of Cybrid and Other Supportive Evidence

Swerdlow

2012

Antioxidants & Redox Signaling

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Significance: Mitochondria are currently believed to play an important role in the neurodysfunction and neurodegeneration that underlie Parkinson's disease (PD). Recent Advances: While it increasingly appears that mitochondrial dysfunction in PD can have different causes, it has been proposed that mitochondrial DNA (mtDNA) may account for or drive mitochondrial dysfunction in the majority of the cases. If correct, the responsible mtDNA signatures could represent acquired mutations, inherited mutations, or population-distributed polymorphisms. Critical Issues and Future Directions: This review discusses the case for mtDNA as a key mediator of PD, and especially focuses on data from studies of PD cytoplasmic hybrid (cybrid) cell lines. Antioxid. Redox Signal. 16, 950-964.

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Somatic mitochondrial DNA mutations in early parkinson and incidental lewy body disease

Lin

Cantuti-Castelvetri

Zheng

et al. 2012

Annals of Neurology

113

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Somatic mutations in mitochondrial DNA (mtDNA) are hypothesized to play a role in Parkinson disease (PD), but large increases in mtDNA mutations have not previously been found in PD, potentially because neurons with high mutation levels degenerate and thus are absent in late-stage tissue. To address this issue, we studied early stage PD cases and cases of incidental Lewy body disease (ILBD), which is thought to represent presymptomatic PD. We show for the first time that mtDNA mutation levels in substantia nigra (SN) neurons are significantly elevated in this group of early PD and ILBD cases.

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Somatic mitochondrial DNA mutations in cortex and substantia nigra in aging and Parkinson’s disease

Cited by 103 publications

References 61 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?

Does Mitochondrial DNA Play a Role in Parkinson's Disease? A Review of Cybrid and Other Supportive Evidence

Somatic mitochondrial DNA mutations in early parkinson and incidental lewy body disease

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