scholarly journals Mitochondrial DNA mutations in disease and aging

2011 ◽  
Vol 193 (5) ◽  
pp. 809-818 ◽  
Author(s):  
Chan Bae Park ◽  
Nils-Göran Larsson
Keyword(s):  
Mitochondrial Dna ◽  
Oxidative Phosphorylation ◽  
Molecular Level ◽  
Mitochondrial Diseases ◽  
Mitochondrial Genetics ◽  
Replication Errors ◽  
Mtdna Mutations ◽  
Accumulated Damage ◽  
Dna Mutations ◽  
Human Pathology

The small mammalian mitochondrial DNA (mtDNA) is very gene dense and encodes factors critical for oxidative phosphorylation. Mutations of mtDNA cause a variety of human mitochondrial diseases and are also heavily implicated in age-associated disease and aging. There has been considerable progress in our understanding of the role for mtDNA mutations in human pathology during the last two decades, but important mechanisms in mitochondrial genetics remain to be explained at the molecular level. In addition, mounting evidence suggests that most mtDNA mutations may be generated by replication errors and not by accumulated damage.

Do mitochondrial DNA mutations play the key role in chronification of sterile inflammation? Special focus on atherosclerosis

2020 ◽  
Vol 26 ◽  
Author(s):  
Alexander N. Orekhov ◽  
Elena V. Gerasimova ◽  
Vasily N. Sukhorukov ◽  
Anastasia V. Poznyak ◽  
Nikita G. Nikiforov
Keyword(s):  
Innate Immunity ◽  
Mitochondrial Dna ◽  
Low Density Lipoprotein ◽  
Atherosclerotic Lesion ◽  
Density Lipoprotein ◽  
Sterile Inflammation ◽  
Special Focus ◽  
Mitochondrial Dysfunctions ◽  
Mtdna Mutations ◽  
Dna Mutations

Background: The elucidation of mechanisms implicated in the chronification of inflammation is able to shed the light on the pathogenesis of disorders that are responsible for the majority of the incidence of disease and deaths, and also causes of ageing. Atherosclerosis is an example of the most significant inflammatory pathology. The inflammatory response of innate immunity is implicated in the development of atherosclerosis arising locally or focally. Modified low-density lipoprotein (LDL) was regarded as the trigger for this response. No atherosclerotic changes in the arterial wall occur due to the quick decrease in inflammation rate. Nonetheless, the atherosclerotic lesion formation can be a result of the chronification of local inflammation, which, in turn, is caused by alteration of the response of innate immunity. Objective: In this review, we discussed potential mechanisms of the altered response of the immunity in atherosclerosis with a particular emphasis on mitochondrial dysfunctions. Conclusion: A few mitochondrial dysfunctions can be caused by the mitochondrial DNA (mtDNA) mutations. Moreover, mtDNA mutations were found to affect the development of defective mitophagy. Modern investigations have demonstrated the controlling mitophagy function in the response of the immune system. Therefore, we hypothesized that impaired mitophagy, as a consequence of mutations in mtDNA, can raise a disturbed innate immunity response resulting in the chronification of inflammation in atherosclerosis.

scholarly journals Segregation of mitochondrial DNA (mtDNA) in human oocytes and in animal models of mtDNA disease: clinical implications

Reproduction ◽  
2002 ◽  
pp. 751-755 ◽  
Author(s):  
J Poulton ◽  
DR Marchington
Keyword(s):  
Mitochondrial Dna ◽  
Antenatal Diagnosis ◽  
Mitochondrial Diseases ◽  
Management Options ◽  
Mtdna Mutations ◽  
Mendelian Disorders ◽  
Leigh’S Syndrome ◽  
Normal Individuals ◽  
Substantial Progress ◽  
Chorionic Villous Sampling

Mitochondrial DNA (mtDNA) is almost entirely maternally inherited. Thousands of copies of mtDNA are present in every nucleated cell and in most normal individuals these are virtually identical (homoplasmy). mtDNA diseases may be caused by mutations in either mitochondrial or nuclear genes and, hence, give rise to maternal or autosomal patterns of inheritance. Antenatal diagnosis of mitochondrial diseases based on chorionic villous sampling is available for Mendelian disorders and the syndromes caused by mutations at bp 8993 (associated with Leigh's syndrome and neurogenic weakness, ataxia and retinitis pigmentosa (NARP)). However, prenatal diagnosis of many other maternally inherited mtDNA diseases is less reliable because it is not possible to predict with confidence the way in which heteroplasmic mtDNA mutations segregate within tissues and find clinical expression. This review focuses on the substantial progress in genetics that has been made recently, and on the management options that clinicians can offer to families.

Senescence is coupled to induction of an oxidative phosphorylation stress response by mitochondrial DNA mutations in Neurospora

1995 ◽  
Vol 73 (S1) ◽  
pp. 198-204 ◽  
Author(s):  
Helmut Bertrand
Keyword(s):  
Mitochondrial Dna ◽  
Stress Response ◽  
Oxidative Phosphorylation ◽  
Strictly Aerobic ◽  
Wild Type ◽  
Mitochondrial Mutations ◽  
Mitochondrial Mutation ◽  
Mitochondrial Dna Mutations ◽  
Dna Mutations ◽  
Mitochondrial Dnas

In Neurospora and other genera of filamentous fungi, the occurrence of a mutation affecting one or several genes on the chromosome of a single mitochondrion can trigger the gradual displacement of wild-type mitochondrial DNA by mutant molecules in asexually propagated cultures. As this displacement progresses, the cultures senesce gradually and die if the mitochondrial mutation is lethal, or develop respiratory deficiencies if the mutation is nonlethal. Mitochondrial mutations that elicit the displacement of wild-type mitochondrial DNAs are said to be "suppressive." In the strictly aerobic fungi, suppressiveness appears to be associated exclusively with mutations that diminish cytochrome-mediated mitochondrial redox functions and, thus, curtail oxidative phosphorylation. In Neurospora, suppressiveness is connected to a regulatory system through which cells respond to chemical or genetic insults to the mitochondrial electron-transport system by increasing the number of mitochondria approximately threefold. Mutant alleles of two nuclear genes, osr-1 and osr-2, affect this stress response and abrogate the suppressiveness of mitochondrial mutations. Therefore, we propose that mitochondrial mutations are suppressive because their phenotypic effect is limited to the organelles within which the mutant DNA is located. Consequently, mitochondria that are "homozygous" for a mutant allele are functionally crippled and are induced to proliferate more rapidly than the normal mitochondria with which they coexist in a common protoplasm. While this model provides a plausible explanation for the suppressiveness of mitochondrial mutations in the strictly aerobic fungi, it may not account for the biased transmission of mutant mitochondrial DNAs in the facultatively anaerobic yeasts. Key words: mitochondria, mitochondrial DNA, mutations, suppressiveness, oxidative phosphorylation, stress response.

scholarly journals Defective Oxidative Phosphorylation in Thyroid Oncocytic Carcinoma Is Associated with Pathogenic Mitochondrial DNA Mutations Affecting Complexes I and III

2006 ◽  
Vol 66 (12) ◽  
pp. 6087-6096 ◽  
Author(s):  
Elena Bonora ◽  
Anna Maria Porcelli ◽  
Giuseppe Gasparre ◽  
Annalisa Biondi ◽  
Anna Ghelli ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Oxidative Phosphorylation ◽  
Oncocytic Carcinoma ◽  
Mitochondrial Dna Mutations ◽  
Dna Mutations

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

2011 ◽  
Vol 2011 ◽  
pp. 1-9 ◽  
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.

scholarly journals Bottleneck and selection in the germline and maternal age influence transmission of mitochondrial DNA in human pedigrees

2019 ◽  
Vol 116 (50) ◽  
pp. 25172-25178 ◽  
Author(s):  
Arslan A. Zaidi ◽  
Peter R. Wilton ◽  
Marcia Shu-Wei Su ◽  
Ian M. Paul ◽  
Barbara Arbeithuber ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
De Novo ◽  
Mitochondrial Diseases ◽  
Clinical Genetics ◽  
De Novo Mutations ◽  
Germline Development ◽  
Older Mothers ◽  
Somatic Development ◽  
Mtdna Mutations ◽  
Mother’S Age

Heteroplasmy—the presence of multiple mitochondrial DNA (mtDNA) haplotypes in an individual—can lead to numerous mitochondrial diseases. The presentation of such diseases depends on the frequency of the heteroplasmic variant in tissues, which, in turn, depends on the dynamics of mtDNA transmissions during germline and somatic development. Thus, understanding and predicting these dynamics between generations and within individuals is medically relevant. Here, we study patterns of heteroplasmy in 2 tissues from each of 345 humans in 96 multigenerational families, each with, at least, 2 siblings (a total of 249 mother–child transmissions). This experimental design has allowed us to estimate the timing of mtDNA mutations, drift, and selection with unprecedented precision. Our results are remarkably concordant between 2 complementary population-genetic approaches. We find evidence for a severe germline bottleneck (7–10 mtDNA segregating units) that occurs independently in different oocyte lineages from the same mother, while somatic bottlenecks are less severe. We demonstrate that divergence between mother and offspring increases with the mother’s age at childbirth, likely due to continued drift of heteroplasmy frequencies in oocytes under meiotic arrest. We show that this period is also accompanied by mutation accumulation leading to more de novo mutations in children born to older mothers. We show that heteroplasmic variants at intermediate frequencies can segregate for many generations in the human population, despite the strong germline bottleneck. We show that selection acts during germline development to keep the frequency of putatively deleterious variants from rising. Our findings have important applications for clinical genetics and genetic counseling.

scholarly journals Bcl-2 Suppresses Oxidative Phosphorylation Defects Caused by Mitochondrial DNA Mutations

2001 ◽  
Vol 1 ◽  
pp. 39-39 ◽  
Author(s):  
Giovanni Manfredi ◽  
Jennifer Q. Kwong ◽  
Jose A. Oca-Cossio ◽  
Marilena D. Aurelio ◽  
Carl D. Gajewsky ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Oxidative Phosphorylation ◽  
Mitochondrial Dna Mutations ◽  
Dna Mutations
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