scholarly journals A Brief History of Mitochondrial Pathologies

2019 ◽  
Vol 20 (22) ◽  
pp. 5643 ◽  
Author(s):  
Salvatore DiMauro
Keyword(s):  
Mitochondrial Dna ◽  
Large Scale ◽  
Nuclear Dna ◽  
Fibroblast Cell ◽  
Histochemical Staining ◽  
The Novel ◽  
Mtdna Mutations ◽  
Mendelian Genetics ◽  
History Of ◽  
Experimental Approaches

The history of “mitochondrial pathologies”, namely genetic pathologies affecting mitochondrial metabolism because of mutations in nuclear DNA-encoded genes for proteins active inside mitochondria or mutations in mitochondrial DNA-encoded genes, began in 1988. In that year, two different groups of researchers discovered, respectively, large-scale single deletions of mitochondrial DNA (mtDNA) in muscle biopsies from patients with “mitochondrial myopathies” and a point mutation in the mtDNA gene for subunit 4 of NADH dehydrogenase (MTND4), associated with maternally inherited Leber’s hereditary optic neuropathy (LHON). Henceforth, a novel conceptual “mitochondrial genetics”, separate from mendelian genetics, arose, based on three features of mtDNA: (1) polyplasmy; (2) maternal inheritance; and (3) mitotic segregation. Diagnosis of mtDNA-related diseases became possible through genetic analysis and experimental approaches involving histochemical staining of muscle or brain sections, single-fiber polymerase chain reaction (PCR) of mtDNA, and the creation of patient-derived “cybrid” (cytoplasmic hybrid) immortal fibroblast cell lines. The availability of the above-mentioned techniques along with the novel sensitivity of clinicians to such disorders led to the characterization of a constantly growing number of pathologies. Here is traced a brief historical perspective on the discovery of autonomous pathogenic mtDNA mutations and on the related mendelian pathology altering mtDNA integrity.

Abstract 17097: Non-Synonymous Mitochondrial DNA Variants Are Common in Myocardial Tissue of Heart Failure Patients

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Pappu Ananya ◽  
Michael Binder ◽  
Yang Wanjun ◽  
Rebecca McClellan ◽  
Brittney Murray ◽  
...  
Keyword(s):  
Heart Failure ◽  
Mitochondrial Dna ◽  
Nuclear Dna ◽  
Left Ventricular ◽  
Individual Risk ◽  
Myocardial Tissue ◽  
Mtdna Mutation ◽  
Mtdna Mutations ◽  
Ventricular Tissue ◽  
Mtdna Variants

Introduction: Mitochondrial heart disease due to pathogenic mitochondrial DNA (mtDNA) mutations can present as hypertrophic or dilated cardiomyopathy, ventricular arrhythmias and conduction disease. It is estimated that the mutation rate of mtDNA is 10 to 20-fold higher than that of nuclear DNA genes due to damage from reactive oxygen species released as byproducts during oxidative phosphorylation. When a new mtDNA mutation arises, it creates an intracellular heteroplasmic mixture of mutant and normal mtDNAs, called heteroplasmy. Heteroplasmy levels can vary in various tissues and examining mtDNA variants in blood may not be representative for the heart. The frequency of pathogenic mtDNA variants in myocardial tissues in unknown. Hypothesis: Human ventricular tissue may contain mtDNA mutations which can lead to alterations in mitochondrial function and increase individual risk for heart failure. Methods: Mitochondrial DNA was isolated from 61 left ventricular myocardial samples obtained from failing human hearts at the time of transplantation. mtDNA was sequenced with 23 primer pairs. In silico prediction of non-conservative missense variants was performed via PolyPhen-2. Heteroplasmy levels of variants predicted to be pathogenic were quantified using allele-specific ARMS-PCR. Results: We identified 21 mtDNA non-synonymous variants predicted to be pathogenic in 17 hearts. Notably, one heart contained four pathogenic mtDNA variants (ATP6: p.M104; ND5: p.P265S; ND4: p.N390S and p.L445F). Heteroplasmy levels exceeded 90% for all four variants in myocardial tissue and were significantly lower in blood. No pathogenic mtDNA variants were identified in 44 hearts. Hearts with mtDNA mutations had higher levels of myocardial GDF-15 (growth differentiation factor-15; 6.2±2.3 vs. 1.3±0.18, p=0.045), an established serum biomarker in various mitochondrial diseases. Conclusions: Non-synonymous mtDNA variants predicted to be pathogenic are common in human left ventricular tissue and may be an important modifier of the heart failure phenotype. Future studies are necessary to correlate myocardial mtDNA mutations with cardiovascular outcomes and to assess whether serum GDF-15 allows identifying patients with myocardial mtDNA mutations.

Abstract 206: Accumulation of Mitochondrial DNA Mutations Impairs Survival, Proliferation, and Differentiation of Cardiac Progenitor Cells

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Amabel M Orogo ◽  
Dieter A Kubli ◽  
Anne N Murphy ◽  
Åsa B Gustafsson
Keyword(s):  
Mitochondrial Dna ◽  
Progenitor Cells ◽  
Mitochondrial Biogenesis ◽  
Nuclear Dna ◽  
Critical Role ◽  
Chemotherapeutic Agents ◽  
Cardiac Progenitor Cells ◽  
Mtdna Mutations ◽  
Differentiation Medium ◽  
Proliferation And Differentiation

Activation and participation of cardiac progenitor cells (CPCs) in regeneration are critical for effective repair in the wake of pathologic injury. Stem cell activation and commitment involve increased energy demand and mitochondrial biogenesis. To date, little attention has been paid to the importance of mitochondria in CPC survival, proliferation and differentiation. CPC function is reduced with age but the underlying mechanism is still unclear. Mitochondrial DNA (mtDNA) is more susceptible to oxidative attacks than nuclear DNA due to its proximity to the mitochondrial respiratory chain and lack of protective histone-like proteins. With age, mtDNA accumulates mutations that can impair mitochondrial respiration and increase ROS production. In this study, we examined the effects of accumulating mtDNA mutations on CPC proliferation and survival. We have found that incubation of uncommitted c-kit+ CPCs in differentiation medium increased mitochondrial mass and expansion of the mitochondrial network, which correlated with increased cell size and expression of cardiac lineage commitment markers. Differentiation activated mitochondrial biogenesis, increased mtDNA copy number, and enhanced oxidative capacity and cellular ATP levels in CPCs. To investigate the effect of mtDNA mutations and aging on CPC survival and function, we utilized a mouse model in which a mutation in the mtDNA polymerase γ (POLG m/m ) leads to accumulation of mtDNA mutations, mitochondrial dysfunction, and accelerated aging. Isolated CPCs from hearts of 2-month old POLG m/m mice had reduced proliferation and were more susceptible to oxidative stress and chemotherapeutic agents compared to WT CPCs. The majority of POLG m/m CPCs contained fragmented mitochondria as shown by immunostaining. Incubation in differentiation medium resulted in fewer GATA-4 positive POLG m/m CPCs compared to WT CPCs. The reduced differentiation in these POLG m/m CPCs correlated with reduced PGC-1α expression and OXPHOS protein levels, suggesting that mitochondrial biogenesis is impaired. These data demonstrate that mitochondria play a critical role in CPC function, and accumulation of mtDNA mutations impairs CPC function and reduces their repair potential.

Oxidative Stress, Mitochondrial DNA Mutation, and Impairment of Antioxidant Enzymes in Aging

2002 ◽  
Vol 227 (9) ◽  
pp. 671-682 ◽  
Author(s):  
Yau-Huei Wei ◽  
Hsin-Chen Lee
Keyword(s):  
Oxidative Stress ◽  
Mitochondrial Dna ◽  
Antioxidant Enzymes ◽  
Oxidative Damage ◽  
Large Scale ◽  
Wide Spectrum ◽  
Radical Scavenging ◽  
Mtdna Mutations ◽  
Enhanced Production ◽  
Age Related

Mitochondria do not only produce less ATP, but they also increase the production of reactive oxygen species (ROS) as byproducts of aerobic metabolism in the aging tissues of the human and animals. It is now generally accepted that aging-associated respiratory function decline can result in enhanced production of ROS in mitochondria. Moreover, the activities of free radical-scavenging enzymes are altered in the aging process. The concurrent age-related changes of these two systems result in the elevation of oxidative stress in aging tissues. Within a certain concentration range, ROS may induce stress response of the cells by altering expression of respiratory genes to uphold the energy metabolism to rescue the cell. However, beyond the threshold, ROS may cause a wide spectrum of oxidative damage to various cellular components to result in cell death or elicit apoptosis by induction of mitochondrial membrane permeability transition and release of apoptogenic factors such as cytochrome c. Moreover, oxidative damage and large-scale deletion and duplication of mitochondrial DNA (mtDNA) have been found to increase with age in various tissues of the human. Mitochondria act like a biosensor of oxidative stress and they enable cell to undergo changes in aging and age-related diseases. On the other hand, it has recently been demonstrated that impairment in mitochondrial respiration and oxidative phosphorylation elicits an increase in oxidative stress and causes a host of mtDNA rearrangements and deletions. Here, we review work done in the past few years to support our view that oxidative stress and oxidative damage are a result of concurrent accumulation of mtDNA mutations and defective antioxidant enzymes in human aging.

scholarly journals Nuclear DNA-encoded fragments of mitochondrial DNA (mtDNA) confound analysis of selection of mtDNA mutations in human primordial germ cells.

2021 ◽  
Author(s):  
Melissa Franco ◽  
Zoe Fleischmann ◽  
Sofia Annis ◽  
Konstantin Khrapko ◽  
Jonathan L. Tilly ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Germ Cells ◽  
Nuclear Dna ◽  
Mutational Analysis ◽  
Primordial Germ Cells ◽  
Purifying Selection ◽  
Mutational Pressure ◽  
Mtdna Mutations ◽  
Reported Effect ◽  
Selection Of

The resilience of the mitochondrial genome to a high mutational pressure depends, in part, on purifying selection against detrimental mutations in the germline. It is crucial to understand the mechanisms of this process. Recently, Floros et al. concluded that much of the purifying selection takes place during the proliferation of primordial germ cells (PGCs) because, according to their analysis, the synonymity of mutations in late PGCs was seemingly increased compared to those in early PGCs. We re-analyzed the Floros et al. mutational data and discovered a high proportion of sequence variants that are not true mutations, but originate from NUMTs, the latter of which are segments of mitochondrial DNA (mtDNA) inserted into nuclear DNA, up to millions of years ago. This is a well-known artifact in mtDNA mutational analysis. Removal of these artifacts from the Floros et al. dataset abolishes the reported effect of purifying selection in PGCs. We therefore conclude that the mechanism of germline selection of mtDNA mutations remains open for debate, and more research is needed to fully elucidate the timing and nature of this process.

scholarly journals A pedigree-based analysis of mitochondrial DNA diversity in a dog population on the example of German Hovawarts

2015 ◽  
Vol 58 (2) ◽  
pp. 335-342
Author(s):  
S. Zielińska ◽  
I. Głażewska
Keyword(s):  
Mitochondrial Dna ◽  
Pedigree Analysis ◽  
Mtdna Mutations ◽  
Dna Diversity ◽  
Mtdna Inheritance ◽  
Mtdna Haplotypes ◽  
History Of ◽  
Pedigree Errors ◽  
Mtdna Diversity ◽  
New Mutations

Abstract. The purpose of the article is to illustrate the use of pedigree analysis to evaluate mtDNA diversity in a selected population of pedigree dogs, to describe the paths of mtDNA inheritance and to estimate the spread of potential pedigree errors or mutations that occurred in different generations of ancestors. Hovawart, old German breed, was used as an example. The number and frequencies of mtDNA haplotypes were calculated based on numbers of dam lines and their representatives. The scale of potential errors in calculations that can result from pedigree errors or from new mutations in ancestors from the 5th or 10th ancestral generation was evaluated. The analysis included 368 breeding bitches from four German kennel organizations. The bitches represented three dam lines, with the Ho1, Ho2 and HoU mtDNA haplotypes. Significant differences in the frequency of the haplotypes in the population, from 0.27 to 73.37 %, and among kennel organizations and regions of the country were recorded. Considerable differences in the scale of potential errors in calculations arising from mtDNA mutations or pedigree errors were noted between 0.27 and 28.69 %, depending on the number of representatives of the subline in which the error appeared and the generation taken into account in the simulations. The study revealed an interesting paradox: although the differences between the haplotypes are the result of events (mutations) from thousands of years ago, the number and the frequencies of the haplotypes in the population are the result of the modern history of the population and current breeding policy.

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

Biomedicines ◽  
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.

scholarly journals Sibling rivalry versus mother's curse: can kin competition facilitate a response to selection on male mitochondria?

2020 ◽  
Vol 287 (1930) ◽  
pp. 20200575 ◽  
Author(s):  
Thomas A. Keaney ◽  
Heidi W. S. Wong ◽  
Damian K. Dowling ◽  
Therésa M. Jones ◽  
Luke Holman
Keyword(s):  
Mitochondrial Dna ◽  
Kin Selection ◽  
Nuclear Dna ◽  
Genetic Effect ◽  
Adult Survival ◽  
Direct Selection ◽  
Mitochondrial Haplotype ◽  
Social Partner ◽  
Mtdna Mutations ◽  
Indirect Genetic Effect

Assuming that fathers never transmit mitochondrial DNA (mtDNA) to their offspring, mitochondrial mutations that affect male fitness are invisible to direct selection on males, leading to an accumulation of male-harming alleles in the mitochondrial genome (mother's curse). However, male phenotypes encoded by mtDNA can still undergo adaptation via kin selection provided that males interact with females carrying related mtDNA, such as their sisters. Here, using experiments with Drosophila melanogaster carrying standardized nuclear DNA but distinct mitochondrial DNA, we test whether the mitochondrial haplotype carried by interacting pairs of larvae affects survival to adulthood, as well as the fitness of the adults. Although mtDNA had no detectable direct or indirect genetic effect on larva-to-adult survival, the fitness of male and female adults was significantly affected by their own mtDNA and the mtDNA carried by their social partner in the larval stage. Thus, mtDNA mutations that alter the effect of male larvae on nearby female larvae (which often carry the same mutation, due to kinship) could theoretically respond to kin selection. We discuss the implications of our findings for the evolution of mitochondria and other maternally inherited endosymbionts.

scholarly journals The innate immune system in host mice targets cells with allogenic mitochondrial DNA

2010 ◽  
Vol 207 (11) ◽  
pp. 2297-2305 ◽  
Author(s):  
Kaori Ishikawa ◽  
Noriko Toyama-Sorimachi ◽  
Kazuto Nakada ◽  
Mami Morimoto ◽  
Hirotake Imanishi ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Immune System ◽  
Innate Immune System ◽  
Nuclear Dna ◽  
Embryonic Stem ◽  
Innate Immune ◽  
Mouse Strains ◽  
Mtdna Mutations ◽  
Aged Subjects ◽  
Dependent Pathway

Mitochondrial DNA (mtDNA) has been proposed to be involved in respiratory function, and mtDNA mutations have been associated with aging, tumors, and various disorders, but the effects of mtDNA imported into transplants from different individuals or aged subjects have been unclear. We examined this issue by generating trans-mitochondrial tumor cells and embryonic stem cells that shared the syngenic C57BL/6 (B6) strain–derived nuclear DNA background but possessed mtDNA derived from allogenic mouse strains. We demonstrate that transplants with mtDNA from the NZB/B1NJ strain were rejected from the host B6 mice, not by the acquired immune system but by the innate immune system. This rejection was caused partly by NK cells and involved a MyD88-dependent pathway. These results introduce novel roles of mtDNA and innate immunity in tumor immunology and transplantation medicine.

Metafiction and the Postwar Novel

2021 ◽  
Author(s):  
Andrew Dean
Keyword(s):  
World War Ii ◽  
Large Scale ◽  
The Novel ◽  
Philip Roth ◽  
Miguel De Cervantes ◽  
The Public ◽  
Political Debates ◽  
History Of ◽  
Janet Frame ◽  
The Relationship

This book examines the origins, poetics, and capacities of self-reflexive fiction across the globe after World War II. Focusing on three authors’ careers—J. M. Coetzee, Janet Frame, and Philip Roth—it seeks to circumvent the large-scale theoretical paradigms (such as ‘postmodernism’) that have long been deployed to describe this writing. The book does so by developing new terms for discussing the intimacies of metafictional writing, derived from the writing of Miguel de Cervantes and J. L. Borges. The ‘self of writing’ refers to the figure of the author that a writer may imagine exists independently from discourse. The ‘public author as signature’ represents the public understandings of an author that emerge from biography and the author’s corpus itself. The book shows how these figures of authorship are handled by authors, as they draw on the materials offered by their own corpora and communities of readers. Sometimes, this book shows, authors invent distinctively literary ways of adjudicating enduring political debates: the responsibility of a novelist to the political aspirations of a community, the ability of the novel to pursue justice on behalf of others, and the public good that literature serves. Yet this is not a story of unmitigated success: the book also demonstrates how metafiction can be used as a way to close down interpretive schemes and to avoid contributing to public value. Through a close focus on literary environments, the book ultimately gives a finer-grained account of the history of postwar metafiction, and offers new ways of theorizing the relationship between fiction, life-writing, and literary institutions.

Sign in / Sign up

Export Citation Format

Share Document