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Journal ArticleDOI: 10.1080/00207454.2020.1738433

Elevated serum mitochondrial DNA in females and lack of altered platelet mitochondrial methylation in patients with Parkinson´s disease.

04 Mar 2021-International Journal of Neuroscience (Newcastle University)-Vol. 131, Iss: 3, pp 279-282
Abstract: Purpose: Mitochondrial dysfunction has long been considered in the pathogenesis of Parkinson's disease (PD). This is evident from the presence of mitochondrial DNA deletions in substantia nigra neu...

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Topics: Mitochondrial DNA (61%), Substantia nigra (57%), DNA methylation (56%) ... show more
Citations
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6 results found


Open accessJournal ArticleDOI: 10.3390/IJMS22094594
Andrea Stoccoro1, Fabio Coppedè1Institutions (1)
Abstract: Epigenetic modifications of the nuclear genome, including DNA methylation, histone modifications and non-coding RNA post-transcriptional regulation, are increasingly being involved in the pathogenesis of several human diseases. Recent evidence suggests that also epigenetic modifications of the mitochondrial genome could contribute to the etiology of human diseases. In particular, altered methylation and hydroxymethylation levels of mitochondrial DNA (mtDNA) have been found in animal models and in human tissues from patients affected by cancer, obesity, diabetes and cardiovascular and neurodegenerative diseases. Moreover, environmental factors, as well as nuclear DNA genetic variants, have been found to impair mtDNA methylation patterns. Some authors failed to find DNA methylation marks in the mitochondrial genome, suggesting that it is unlikely that this epigenetic modification plays any role in the control of the mitochondrial function. On the other hand, several other studies successfully identified the presence of mtDNA methylation, particularly in the mitochondrial displacement loop (D-loop) region, relating it to changes in both mtDNA gene transcription and mitochondrial replication. Overall, investigations performed until now suggest that methylation and hydroxymethylation marks are present in the mtDNA genome, albeit at lower levels compared to those detectable in nuclear DNA, potentially contributing to the mitochondria impairment underlying several human diseases.

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Topics: DNA methylation (63%), Mitochondrial DNA (63%), Epigenetics (60%) ... show more

3 Citations


Journal ArticleDOI: 10.1016/J.SCITOTENV.2021.147330
Guoyu Zhou1, Guoyu Zhou2, Qian Zhao3, Qian Zhao2  +9 moreInstitutions (4)
Abstract: Mitochondrial DNA (mtDNA) content alterations are potential mediators of neuronal disorders. However, what effects of mtDNA content are on fluoride-induced neurotoxicity remain elusive. Here, a cross-sectional study was conducted to investigate roles of circulating mtDNA content on associations between fluoride and intelligence quotient (IQ) in 605 children aged 7–13 years from Tianjin, China. We assessed IQ and circulating mtDNA content in peripheral blood through the second edition of Combined Raven's Test-The Rural in China (CRT-RC2) and qRT-PCR methods. National standardized ion selective electrode method was used for fluoride concentrations in drinking water samples from each village and urine samples. Our results showed that the median (interquartile range) of water and urinary fluoride concentrations were 1.00 (0.70–2.20) mg/L and 0.41 (0.15–2.29) mg/L respectively. Water/urinary fluoride concentrations were negatively associated with not only IQ scores but mtDNA content, which in turn was positively linked with odds of children having excellent intelligence (P for trend

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3 Citations


Open accessJournal ArticleDOI: 10.1111/BPA.13012
Zixuan Chen1, Madiha Rasheed1, Yulin Deng1Institutions (1)
20 Aug 2021-Brain Pathology
Abstract: Mitochondrial dysfunction is one of the crucial factors involved in PD's pathogenicity, which emerges from a combination of genetic and environmental factors. These factors cause differential molecular expression in neurons, such as varied transcriptional regulation of genes, elevated oxidative stress, α-synuclein aggregation and endogenous neurotoxins release, which induces epigenetic modifications and triggers energy crisis by damaging mitochondria of the dopaminergic neurons (DN). So far, these events establish a complicated relationship with underlying mechanisms of mitochondrial anomalies in PD, which has remained unclear for years and made PD diagnosis and treatment extremely difficult. Therefore, in this review, we endeavored to discuss the complex association of epigenetic modifications and other associated vital factors in mitochondrial dysfunction. We propose a hypothesis that describes a vicious cycle in which mitochondrial dysfunction and oxidative stress act as a hub for regulating DA neuron's fate in PD. Oxidative stress triggers the release of endogenous neurotoxins (CTIQs) that lead to mitochondrial dysfunction along with abnormal α-synuclein aggregation and epigenetic modifications. These disturbances further intensify oxidative stress and mitochondrial damage, amplifying the synthesis of CTIQs and works vice versa. This vicious cycle may result in the degeneration of DN to hallmark Parkinsonism. Furthermore, we have also highlighted various endogenous compounds and epigenetic marks (neurotoxic and neuroprotective), which may help for devising future diagnostic biomarkers and target specific drugs using novel PD management strategies.

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Topics: Neuroprotection (53%), Mitochondrion (52%)

1 Citations


Open accessJournal ArticleDOI: 10.3390/BIOLOGY10080716
Amit Sharma1, Jens Müller1, Karin Schuetze, Verena Rolfes1  +11 moreInstitutions (3)
28 Jul 2021-Biology
Abstract: Parkinson's disease (PD) is the second most common age-related neurodegenerative disease. Accumulating evidence demonstrates that alpha-synuclein (α-Syn), an apparently predominant neuronal protein, is a major contributor to PD pathology. As α-Syn is also highly abundant in blood, particularly in red blood cells (RBCs) and platelets, this in turn raises the question on the function of presumably dysfunctional α-Syn in "peripheral" cells and its putative effect on the other enclosed constituents. Herein, we detected the internal variance in erythrocytes of PD patients by Raman spectroscopy, but no measurable amount of erythrocytic behavioural change (eryptosis) or any haemoglobin variation was noticed. An elevated level of plasmin-antiplasmin complexes (PAP) was observed in the plasma of PD patients, indicating activation of the fibrinolytic system, but platelet activation after thrombin stimulation was not altered. Sex-specific patterns were noticed for blood coagulation factor XIII and factor XII activity in PD patients. Additionally, the alterations in homocysteine levels which have often been observed in PD patients were found to be independent from L-DOPA usage and PAP levels. Furthermore, a selective gene expression analysis identified subsets of genes related to different blood-associated compartments (RBCs, platelets, coagulation-fibrinolysis) also involved in PD-related pathways.

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Topics: Platelet activation (57%), Platelet (53%), Factor XII (53%) ... show more

Open accessJournal ArticleDOI: 10.3390/MEDICINA57090928
Abstract: Background and Objectives. The importance of mitochondria in inflammatory pathologies, besides providing energy, is associated with the release of mitochondrial damage products, such as mitochondrial DNA (mt-DNA), which may perpetuate inflammation. In this review, we aimed to show the importance of mitochondria, as organelles that produce energy and intervene in multiple pathologies, focusing mainly in COVID-19 and using multiple molecular mechanisms that allow for the replication and maintenance of the viral genome, leading to the exacerbation and spread of the inflammatory response. The evidence suggests that mitochondria are implicated in the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which forms double-membrane vesicles and evades detection by the cell defense system. These mitochondrion-hijacking vesicles damage the integrity of the mitochondrion's membrane, releasing mt-DNA into circulation and triggering the activation of innate immunity, which may contribute to an exacerbation of the pro-inflammatory state. Conclusions. While mitochondrial dysfunction in COVID-19 continues to be studied, the use of mt-DNA as an indicator of prognosis and severity is a potential area yet to be explored.

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Topics: Mitochondrion (53%), Mitochondrial DNA (53%)

References
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14 results found


Journal ArticleDOI: 10.1126/SCIENCE.6823561
25 Feb 1983-Science
Abstract: Four persons developed marked parkinsonism after using an illicit drug intravenously. Analysis of the substance injected by two of these patients revealed primarily 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) with trace amounts of 1-methyl-4-phenyl-4-propionoxy-piperidine (MPPP). On the basis of the striking parkinsonian features observed in our patients, and additional pathological data from one previously reported case, it is proposed that this chemical selectively damages cells in the substantia nigra.

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Topics: Parkinsonism (58%), MPTP (57%), MPTP Poisoning (54%) ... show more

4,536 Citations


Journal ArticleDOI: 10.1016/S0140-6736(89)92366-0
Anthony H.V. Schapira1, JM Cooper, D. Dexter, Peter Jenner  +2 moreInstitutions (1)
03 Jun 1989-The Lancet
Topics: NAD(P)H Dehydrogenase (Quinone) (59%), Substantia nigra (56%), Mitochondrion (54%) ... show more

1,447 Citations


Journal ArticleDOI: 10.1038/NG1769
09 Apr 2006-Nature Genetics
Abstract: Here we show that in substantia nigra neurons from both aged controls and individuals with Parkinson disease, there is a high level of deleted mitochondrial DNA (mtDNA) (controls, 43.3% ± 9.3%; individuals with Parkinson disease, 52.3% ± 9.3%). These mtDNA mutations are somatic, with different clonally expanded deletions in individual cells, and high levels of these mutations are associated with respiratory chain deficiency. Our studies suggest that somatic mtDNA deletions are important in the selective neuronal loss observed in brain aging and in Parkinson disease.

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Topics: Substantia nigra (59%), Mitochondrial DNA (52%)

1,267 Citations


Open accessJournal ArticleDOI: 10.1074/JBC.M710012200
Abstract: α-Synuclein, a protein implicated in the pathogenesis of Parkinson disease (PD), is thought to affect mitochondrial functions, although the mechanisms of its action remain unclear. In this study we show that the N-terminal 32 amino acids of human α-synuclein contain cryptic mitochondrial targeting signal, which is important for mitochondrial targeting of α-synuclein. Mitochondrial imported α-synuclein is predominantly associated with the inner membrane. Accumulation of wild-type α-synuclein in the mitochondria of human dopaminergic neurons caused reduced mitochondrial complex I activity and increased production of reactive oxygen species. However, these defects occurred at an early time point in dopaminergic neurons expressing familial α-synuclein with A53T mutation as compared with wild-type α-synuclein. Importantly, α-synuclein that lacks mitochondrial targeting signal failed to target to the mitochondria and showed no detectable effect on complex I function. The PD relevance of these results was investigated using mitochondria of substantia nigra, striatum, and cerebellum of postmortem late-onset PD and normal human brains. Results showed the constitutive presence of ∼14-kDa α-synuclein in the mitochondria of all three brain regions of normal subjects. Mitochondria of PD-vulnerable substantia nigra and striatum but not cerebellum from PD subjects showed significant accumulation of α-synuclein and decreased complex I activity. Analysis of mitochondria from PD brain and α-synuclein expressing dopaminergic neuronal cultures using blue native gel electrophoresis and immunocapture technique showed the association of α-synuclein with complex I. These results provide evidence that mitochondrial accumulated α-synuclein may interact with complex I and interfere with its functions.

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Topics: Substantia nigra (60%), Mitochondrion (56%), Alpha-synuclein (54%) ... show more

794 Citations


Journal ArticleDOI: 10.1016/S0140-6736(89)90291-2
01 Jul 1989-The Lancet
Topics: Parkinson's disease (53%)

305 Citations


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