scholarly journals What cost mitochondria? The maintenance of functional mitochondrial DNA within and across generations

2014 ◽  
Vol 369 (1646) ◽  
pp. 20130438 ◽  
Author(s):  
Duur K. Aanen ◽  
Johannes N. Spelbrink ◽  
Madeleine Beekman
Keyword(s):  
Mitochondrial Dna ◽  
Somatic Growth ◽  
Mtdna Mutations ◽  
Specific Effects ◽  
Age Related ◽  
Mtdna Replication ◽  
Mtdna Evolution ◽  
Selection For ◽  
Male Specific ◽  
Mtdna Variants

The peculiar biology of mitochondrial DNA (mtDNA) potentially has detrimental consequences for organismal health and lifespan. Typically, eukaryotic cells contain multiple mitochondria, each with multiple mtDNA genomes. The high copy number of mtDNA implies that selection on mtDNA functionality is relaxed. Furthermore, because mtDNA replication is not strictly regulated, within-cell selection may favour mtDNA variants with a replication advantage, but a deleterious effect on cell fitness. The opportunities for selfish mtDNA mutations to spread are restricted by various organism-level adaptations, such as uniparental transmission, germline mtDNA bottlenecks, germline selection and, during somatic growth, regular alternation between fusion and fission of mitochondria. These mechanisms are all hypothesized to maintain functional mtDNA. However, the strength of selection for maintenance of functional mtDNA progressively declines with age, resulting in age-related diseases. Furthermore, organismal adaptations that most probably evolved to restrict the opportunities for selfish mtDNA create secondary problems. Owing to predominantly maternal mtDNA transmission, recombination among mtDNA from different individuals is highly restricted or absent, reducing the scope for repair. Moreover, maternal inheritance precludes selection against mtDNA variants with male-specific effects. We finish by discussing the consequences of life-history differences among taxa with respect to mtDNA evolution and make a case for the use of microorganisms to experimentally manipulate levels of selection.

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.

scholarly journals Case Report: Identification of a Novel Variant (m.8909T>C) of Human Mitochondrial ATP6 Gene and Its Functional Consequences on Yeast ATP Synthase

Life ◽  
2020 ◽  
Vol 10 (9) ◽  
pp. 215
Author(s):  
Qiuju Ding ◽  
Róża Kucharczyk ◽  
Weiwei Zhao ◽  
Alain Dautant ◽  
Shutian Xu ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Atp Synthase ◽  
Atp Synthesis ◽  
Single Individual ◽  
Loss Of Function ◽  
Mtdna Mutations ◽  
Atp6 Gene ◽  
Novel Variant ◽  
Functional Consequences ◽  
Mtdna Variants

With the advent of next generation sequencing, the list of mitochondrial DNA (mtDNA) mutations identified in patients rapidly and continuously expands. They are frequently found in a limited number of cases, sometimes a single individual (as with the case herein reported) and in heterogeneous genetic backgrounds (heteroplasmy), which makes it difficult to conclude about their pathogenicity and functional consequences. As an organism amenable to mitochondrial DNA manipulation, able to survive by fermentation to loss-of-function mtDNA mutations, and where heteroplasmy is unstable, Saccharomyces cerevisiae is an excellent model for investigating novel human mtDNA variants, in isolation and in a controlled genetic context. We herein report the identification of a novel variant in mitochondrial ATP6 gene, m.8909T>C. It was found in combination with the well-known pathogenic m.3243A>G mutation in mt-tRNALeu. We show that an equivalent of the m.8909T>C mutation compromises yeast adenosine tri-phosphate (ATP) synthase assembly/stability and reduces the rate of mitochondrial ATP synthesis by 20–30% compared to wild type yeast. Other previously reported ATP6 mutations with a well-established pathogenicity (like m.8993T>C and m.9176T>C) were shown to have similar effects on yeast ATP synthase. It can be inferred that alone the m.8909T>C variant has the potential to compromise human health.

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 The costs of being male: are there sex-specific effects of uniparental mitochondrial inheritance?

2014 ◽  
Vol 369 (1646) ◽  
pp. 20130440 ◽  
Author(s):  
Madeleine Beekman ◽  
Damian K. Dowling ◽  
Duur K. Aanen
Keyword(s):  
Maternal Inheritance ◽  
Phenotypic Expression ◽  
Natural Populations ◽  
Mtdna Mutations ◽  
Specific Effects ◽  
Mtdna Sequence ◽  
Multiple Copies ◽  
The One ◽  
Mtdna Variants ◽  
Male Expression

Eukaryotic cells typically contain numerous mitochondria, each with multiple copies of their own genome, the mtDNA. Uniparental transmission of mitochondria, usually via the mother, prevents the mixing of mtDNA from different individuals. While on the one hand, this should resolve the potential for selection for fast-replicating mtDNA variants that reduce organismal fitness, maternal inheritance will, in theory, come with another set of problems that are specifically relevant to males. Maternal inheritance implies that the mitochondrial genome is never transmitted through males, and thus selection can target only the mtDNA sequence when carried by females. A consequence is that mtDNA mutations that confer male-biased phenotypic expression will be prone to evade selection, and accumulate. Here, we review the evidence from the ecological, evolutionary and medical literature for male specificity of mtDNA mutations affecting fertility, health and ageing. While such effects have been discovered experimentally in the laboratory, their relevance to natural populations—including the human population—remains unclear. We suggest that the existence of male expression-biased mtDNA mutations is likely to be a broad phenomenon, but that these mutations remain cryptic owing to the presence of counter-adapted nuclear compensatory modifier mutations, which offset their deleterious effects.

scholarly journals Mitochondrial DNA Mutation Detection by Electrospray Mass Spectrometry

2007 ◽  
Vol 53 (2) ◽  
pp. 195-203 ◽  
Author(s):  
Yun Jiang ◽  
Thomas A Hall ◽  
Steven A Hofstadler ◽  
Robert K Naviaux
Keyword(s):  
Mass Spectrometry ◽  
Mitochondrial Dna ◽  
Rflp Analysis ◽  
Endocrine Disorders ◽  
Ion Cyclotron Resonance ◽  
Accurate Identification ◽  
Mtdna Mutations ◽  
Fticr Ms ◽  
Pcr Rflp ◽  
Mtdna Variants

Abstract Background: Mitochondrial DNA (mtDNA) mutations cause a large spectrum of clinically important neurodegenerative, neuromuscular, cardiovascular, and endocrine disorders. We describe the novel application of electrospray ionization Fourier transform ion cyclotron resonance mass spectrometry (ESI-FTICR MS) to the rapid and accurate identification of pathogenic mtDNA variants. Methods: In a blinded study, we used ESI-FTICR MS to analyze 24 unrelated samples of total cellular DNA containing 12 mtDNA variants and compared the results with those obtained by conventional PCR-restriction fragment length polymorphism (PCR-RFLP) analysis and gel electrophoresis. Results: From the 24-sample blinded panel, we correctly identified 12 of the samples as bearing an mtDNA variant and found the remaining 12 samples to have no pathogenic variants. The correlation coefficient between the 2 methods for mtDNA variant detection was 1.0; there were no false positives or false negatives in this sample set. In addition, the ESI-FTICR method identified 4 single-nucleotide polymorphisms (SNP) that had previously been missed by standard PCR-RFLP analysis. Conclusions: ESI-FTICR MS is a rapid, sensitive, and accurate method for the identification and quantification of mtDNA mutations and SNPs.

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 Cell reprogramming shapes the mitochondrial DNA landscape

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Wei Wei ◽  
Daniel J. Gaffney ◽  
Patrick F. Chinnery
Keyword(s):  
Pluripotent Stem Cells ◽  
Single Cells ◽  
Cell Reprogramming ◽  
Protein Coding ◽  
Mtdna Mutations ◽  
Age Related ◽  
Human Ipscs ◽  
Induced Pluripotent ◽  
Mtdna Variants ◽  
Original Donor

AbstractIndividual induced pluripotent stem cells (iPSCs) show considerable phenotypic heterogeneity, but the reasons for this are not fully understood. Comprehensively analysing the mitochondrial genome (mtDNA) in 146 iPSC and fibroblast lines from 151 donors, we show that most age-related fibroblast mtDNA mutations are lost during reprogramming. However, iPSC-specific mutations are seen in 76.6% (108/141) of iPSC lines at a mutation rate of 8.62 × 10−5/base pair. The mutations observed in iPSC lines affect a higher proportion of mtDNA molecules, favouring non-synonymous protein-coding and tRNA variants, including known disease-causing mutations. Analysing 11,538 single cells shows stable heteroplasmy in sub-clones derived from the original donor during differentiation, with mtDNA variants influencing the expression of key genes involved in mitochondrial metabolism and epidermal cell differentiation. Thus, the dynamic mtDNA landscape contributes to the heterogeneity of human iPSCs and should be considered when using reprogrammed cells experimentally or as a therapy.

scholarly journals Mechanisms of Human Mitochondrial DNA Maintenance: The Determining Role of Primary Sequence and Length over Function

1999 ◽  
Vol 10 (10) ◽  
pp. 3345-3356 ◽  
Author(s):  
Carlos T. Moraes ◽  
Lesley Kenyon ◽  
Huiling Hao
Keyword(s):  
Mitochondrial Dna ◽  
Oxidative Phosphorylation ◽  
Copy Number ◽  
Human Cells ◽  
Mtdna Copy Number ◽  
Molecular Features ◽  
Mtdna Replication ◽  
Selection For ◽  
Dna Maintenance

Although the regulation of mitochondrial DNA (mtDNA) copy number is performed by nuclear-coded factors, very little is known about the mechanisms controlling this process. We attempted to introduce nonhuman ape mtDNA into human cells harboring either no mtDNA or mutated mtDNAs (partial deletion and tRNA gene point mutation). Unexpectedly, only cells containing no mtDNA could be repopulated with nonhuman ape mtDNA. Cells containing a defective human mtDNA did not incorporate or maintain ape mtDNA and therefore died under selection for oxidative phosphorylation function. On the other hand, foreign human mtDNA was readily incorporated and maintained in these cells. The suicidal preference for self-mtDNA showed that functional parameters associated with oxidative phosphorylation are less relevant to mtDNA maintenance and copy number control than recognition of mtDNA self-determinants. Non–self-mtDNA could not be maintained into cells with mtDNA even if no selection for oxidative phosphorylation was applied. The repopulation kinetics of several mtDNA forms after severe depletion by ethidium bromide treatment showed that replication and maintenance of mtDNA in human cells are highly dependent on molecular features, because partially deleted mtDNA molecules repopulated cells significantly faster than full-length mtDNA. Taken together, our results suggest that mtDNA copy number may be controlled by competition for limiting levels of trans-acting factors that recognize primarily mtDNA molecular features. In agreement with this hypothesis, marked variations in mtDNA levels did not affect the transcription of nuclear-coded factors involved in mtDNA replication.

scholarly journals Aging and Mitochondrial DNA

2010 ◽  
Vol 3 (1) ◽  
pp. 177 ◽  
Author(s):  
P. Das ◽  
G. Guha
Keyword(s):  
Mitochondrial Dna ◽  
Functional Decline ◽  
Oxygen Species ◽  
Degenerative Diseases ◽  
Mtdna Mutations ◽  
Wide Acceptance ◽  
Age Related ◽  
Transport Chain ◽  
Theory Of Aging ◽  
Cellular Pathology

According to the mitochondrial theory of aging, accrual of mutations in mitochondrial DNA (mtDNA) plays the paramount function in the cellular pathology of aging and in development of age-related degenerative ailments. Reactive oxygen species (ROS), which are byproducts of oxidative phosphorylation (OX-PHOS) in aerobic (mitochondrial) respiration, cause oxidative stress-induced damage to mtDNA. This damaged DNA, whose normal role is to encode proteins many of which are players in the electron transport chain (ETC), now codes for defective proteins. Such faulty proteins lead to a considerable impairment in the efficacy of ETC, thereby generating more ROS, which cause further damage to mtDNA in turn, leading to further defects in proteins, aggravated ETC dysfunction, and even more ROS. Hence, a ‘vicious cycle’ propagates that ultimately directs tissue cells towards structural and functional decline, or in other words, degeneration and aging. However, in spite of a wide acceptance of this theory, there have simultaneously been a considerable number of criticisms against it. This review is aimed at discussing the paradigm of aging and degenerative diseases in light of the mitochondrial paraphernalia, with reference to the evidences in support as well as in antagonism to the mitochondrial theory of aging.Keywords: Aging; Degenerative diseases; mtDNA mutations; ROS; Cell death.© 2011 JSR Publications. ISSN: 2070-0237 (Print); 2070-0245 (Online). All rights reserved.doi:10.3329/jsr.v3i1.5078                J. Sci. Res. 3 (1), 176-186 (2011)

scholarly journals Genetic mosaic analysis of a deleterious mitochondrial DNA mutation in Drosophila reveals novel aspects of mitochondrial regulation and function

2015 ◽  
Vol 26 (4) ◽  
pp. 674-684 ◽  
Author(s):  
Zhe Chen ◽  
Yun Qi ◽  
Stephanie French ◽  
Guofeng Zhang ◽  
Raúl Covian Garcia ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Cytochrome C ◽  
Cytochrome C Oxidase ◽  
Mtdna Mutation ◽  
Mitochondrial Dna Mutation ◽  
Tissue Specific ◽  
Dna Mutation ◽  
Mtdna Mutations ◽  
Genetic Mosaic ◽  
Age Related

Various human diseases are associated with mitochondrial DNA (mtDNA) mutations, but heteroplasmy—the coexistence of mutant and wild-type mtDNA—complicates their study. We previously isolated a temperature-lethal mtDNA mutation in Drosophila, mt:CoIT300I, which affects the cytochrome c oxidase subunit I (CoI) locus. In the present study, we found that the decrease in cytochrome c oxidase (COX) activity was ascribable to a temperature-dependent destabilization of cytochrome a heme. Consistently, the viability of homoplasmic flies at 29°C was fully restored by expressing an alternative oxidase, which specifically bypasses the cytochrome chains. Heteroplasmic flies are fully viable and were used to explore the age-related and tissue-specific phenotypes of mt:CoIT300I. The proportion of mt:CoIT300I genome remained constant in somatic tissues along the aging process, suggesting a lack of quality control mechanism to remove defective mitochondria containing a deleterious mtDNA mutation. Using a genetic scheme that expresses a mitochondrially targeted restriction enzyme to induce tissue-specific homoplasmy in heteroplasmic flies, we found that mt:CoIT300I homoplasmy in the eye caused severe neurodegeneration at 29°C. Degeneration was suppressed by improving mitochondrial Ca2+ uptake, suggesting that Ca2+ mishandling contributed to mt:CoIT300I pathogenesis. Our results demonstrate a novel approach for Drosophila mtDNA genetics and its application in modeling mtDNA diseases.

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