Biocomplexity and Fractality in the Search of Biomarkers of Aging and Pathology: Mitochondrial DNA Profiling of Parkinson’s Disease

Increasing evidence implicates mitochondrial dysfunction in the etiology of Parkinson’s disease (PD). Mitochondrial DNA (mtDNA) mutations are considered a possible cause and this mechanism might be shared with the aging process and with other age-related neurodegenerative disorders such as Alzheimer’s disease (AD). We have recently proposed a computerized method for mutated mtDNA characterization able to discriminate between AD and aging. The present study deals with mtDNA mutation-based profiling of PD. Peripheral blood mtDNA sequences from late-onset PD patients and age-matched controls were analyzed and compared to the revised Cambridge Reference Sequence (rCRS). The chaos game representation (CGR) method, modified to visualize heteroplasmic mutations, was used to display fractal properties of mtDNA sequences and fractal lacunarity analysis was applied to quantitatively characterize PD based on mtDNA mutations. Parameter β, from the hyperbola model function of our lacunarity method, was statistically different between PD and control groups when comparing mtDNA sequence frames corresponding to GenBank np 5713-9713. Our original method, based on CGR and lacunarity analysis, represents a useful tool to analyze mtDNA mutations. Lacunarity parameter β is able to characterize individual mutation profile of mitochondrial genome and could represent a promising index to discriminate between PD and aging.

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Mitochondrial Dysfunction in Parkinson’s Disease: Focus on Mitochondrial DNA

Biomedicines ◽

10.3390/biomedicines8120591 ◽

2020 ◽

Vol 8 (12) ◽

pp. 591

Author(s):

Olga Buneeva ◽

Valerii Fedchenko ◽

Arthur Kopylov ◽

Alexei Medvedev

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Mitochondrial Dna ◽

Mitochondrial Dysfunction ◽

Nuclear Dna ◽

Good Evidence ◽

Inner Mitochondrial Membrane ◽

Mtdna Mutations ◽

Increased Risk ◽

Mtdna Replication

Mitochondria, the energy stations of the cell, are the only extranuclear organelles, containing their own (mitochondrial) DNA (mtDNA) and the protein synthesizing machinery. The location of mtDNA in close proximity to the oxidative phosphorylation system of the inner mitochondrial membrane, the main source of reactive oxygen species (ROS), is an important factor responsible for its much higher mutation rate than nuclear DNA. Being more vulnerable to damage than nuclear DNA, mtDNA accumulates mutations, crucial for the development of mitochondrial dysfunction playing a key role in the pathogenesis of various diseases. Good evidence exists that some mtDNA mutations are associated with increased risk of Parkinson’s disease (PD), the movement disorder resulted from the degenerative loss of dopaminergic neurons of substantia nigra. Although their direct impact on mitochondrial function/dysfunction needs further investigation, results of various studies performed using cells isolated from PD patients or their mitochondria (cybrids) suggest their functional importance. Studies involving mtDNA mutator mice also demonstrated the importance of mtDNA deletions, which could also originate from abnormalities induced by mutations in nuclear encoded proteins needed for mtDNA replication (e.g., polymerase γ). However, proteomic studies revealed only a few mitochondrial proteins encoded by mtDNA which were downregulated in various PD models. This suggests nuclear suppression of the mitochondrial defects, which obviously involve cross-talk between nuclear and mitochondrial genomes for maintenance of mitochondrial functioning.

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Do Somatic Mitochondrial DNA Mutations Contribute to Parkinson's Disease?

Parkinson s Disease ◽

10.4061/2011/659694 ◽

2011 ◽

Vol 2011 ◽

pp. 1-9 ◽

Cited By ~ 1

Author(s):

Joanne Clark ◽

Ying Dai ◽

David K. Simon

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Mitochondrial Dna ◽

Mitochondrial Dysfunction ◽

Point Mutations ◽

Premature Aging ◽

Mtdna Mutations ◽

Dna Mutations ◽

Mitochondrial Dna Polymerase ◽

Mitochondrial Defect

A great deal of evidence supports a role for mitochondrial dysfunction in the pathogenesis of Parkinson's disease (PD), although the origin of the mitochondrial dysfunction in PD remains unclear. Expression of mitochondrial DNA (mtDNA) from PD patients in “cybrid” cell lines recapitulates the mitochondrial defect, implicating a role for mtDNA mutations, but the specific mutations responsible for the mitochondrial dysfunction in PD have been difficult to identify. Somatic mtDNA point mutations and deletions accumulate with age and reach high levels in substantia nigra (SN) neurons. Mutations in mitochondrial DNA polymeraseγ(POLG) that lead to the accumulation of mtDNA mutations are associated with a premature aging phenotype in “mutator” mice, although overt parkinsonism has not been reported in these mice, and with parkinsonism in humans. Together these data support, but do not yet prove, the hypothesis that the accumulation of somatic mtDNA mutations in SN neurons contribute to the pathogenesis of PD.

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Novel mitochondrial DNA mutations in Parkinson's disease

Journal of Neural Transmission ◽

10.1007/s007020200060 ◽

2002 ◽

Vol 109 (5-6) ◽

pp. 721-729 ◽

Cited By ~ 23

Author(s):

G. Richter ◽

A. Sonnenschein ◽

T. Grünewald ◽

H. Reichmann ◽

B. Janetzky

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Mitochondrial Dna ◽

Mitochondrial Dna Mutations ◽

Dna Mutations

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Absence of 4,977-bp deletion of blood cell mitochondrial DNA in patients with young-onset Parkinson's disease

Acta Neurologica Scandinavica ◽

10.1111/j.1600-0404.1995.tb00423.x ◽

2009 ◽

Vol 91 (2) ◽

pp. 149-152 ◽

Cited By ~ 2

Author(s):

D. E. Shan ◽

S. I. Yeh ◽

Y. C. Wan ◽

Y. H. Wei

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Mitochondrial Dna ◽

Blood Cell ◽

Young Onset

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The universal non-neuronal nature of Parkinson's disease: A theory

10.7287/peerj.preprints.1314v1 ◽

2015 ◽

Author(s):

André Valente ◽

Altynay Adilbayeva ◽

Tursonjan Tokay ◽

Albert Rizvanov

Keyword(s):

Gene Expression ◽

Parkinson’S Disease ◽

Parkinson's Disease ◽

Mitochondrial Dna ◽

Late Onset ◽

Clinical Signs ◽

Global Gene Expression ◽

Neuron Death ◽

Hematopoietic Stem ◽

Hematopoietic Stem Cell Niche

Various recent developments of relevance to Parkinson's disease (PD) are discussed and integrated into a comprehensive hypothesis on the nature, origin and inter-cellular mode of propagation of late-onset sporadic PD. We propose to define sporadic PD as a characteristic pathological deviation in the global gene expression program of a cell: the PD expression-state, or PD-state for short. Although a universal cell-generic state, the PD-state deviation would be particularly damaging in a neuronal context, ultimately leading to neuron death and the ensuing observed clinical signs. We review why age accumulated damage caused by oxidative stress in mitochondria could be the trigger for a primordial cell to shift to the PD-state. We put forward hematopoietic cells could be the first to acquire the PD-state, at hematopoiesis, from the disruption in reactive oxygen species (ROS) homeostasis that arises with age in the hematopoietic stem-cell niche. We argue why, nonetheless, such a process is unlikely to explain the shift to the PD-state of all the subsequently affected cells in a patient, thus indicating the existence of a distinct mechanism of propagation of the PD-state. We highlight recent findings on the intercellular exchange of mitochondrial DNA and the ability of mitochondrial DNA to modulate the cellular global gene expression state and propose this could form the basis for the intercellular propagation of the PD-state.

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