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

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.

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

Circulation ◽

10.1161/circ.142.suppl_3.17097 ◽

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.

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

Circulation Research ◽

10.1161/res.115.suppl_1.206 ◽

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.

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

10.1101/2021.10.18.464832 ◽

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.

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

Journal of Experimental Medicine ◽

10.1084/jem.20092296 ◽

2010 ◽

Vol 207 (11) ◽

pp. 2297-2305 ◽

Cited By ~ 30

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.

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Mitochondrial DNA Mutations Induced by Carbon Ions Radiation: A Preliminary Study

Dose-Response ◽

10.1177/1559325818789842 ◽

2018 ◽

Vol 16 (3) ◽

pp. 155932581878984

Author(s):

Yong Chen ◽

Haining Gao ◽

Wenling Ye

Keyword(s):

Mitochondrial Dna ◽

Nuclear Dna ◽

Ion Irradiation ◽

Direct Sequencing ◽

Point Mutations ◽

Heavy Ion ◽

X Rays ◽

Carbon Ions ◽

Mtdna Mutations ◽

Heavy Ion Irradiation

Heavy-ion irradiation-induced nuclear DNA damage and mutations have been studied comprehensively. However, there is no information about the deleterious effect of heavy-ion irradiation on mitochondrial DNA (mtDNA). In this study, 2 typical mtDNA mutations were examined, including 4977 deletions and D310 point mutations. The 4977 deletions were quantified by real-time polymerase chain reaction, and D310 point mutations were analyzed by direct sequencing and a specific enzyme digestion genotyping method. Results showed that carbon ions radiation can induce temporal fluctuation of mtDNA 4977 deletions in 72 hours after irradiation, while survived clones were free from this deletion. Carbon ions induced more D310 mutations than X-rays, and the single-cell heteroplasmy was eliminated. This is the first study investigating mtDNA mutations induced by carbon ions irradiation in vitro. These findings would provide fundamental information for further investigation of radiation-induced mitochondrial biogenesis.

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A Brief History of Mitochondrial Pathologies

International Journal of Molecular Sciences ◽

10.3390/ijms20225643 ◽

2019 ◽

Vol 20 (22) ◽

pp. 5643 ◽

Cited By ~ 4

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.

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Regulation of nuclear epigenome by mitochondrial DNA heteroplasmy

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1906896116 ◽

2019 ◽

Vol 116 (32) ◽

pp. 16028-16035 ◽

Cited By ~ 33

Author(s):

Piotr K. Kopinski ◽

Kevin A. Janssen ◽

Patrick M. Schaefer ◽

Sophie Trefely ◽

Caroline E. Perry ◽

...

Keyword(s):

Mitochondrial Dna ◽

Mitochondrial Function ◽

Nuclear Dna ◽

Phenotypic Variability ◽

Mitochondrial Protein ◽

Mtdna Mutation ◽

Acetyl Coa ◽

Mtdna Mutations ◽

Histone H4 Acetylation ◽

Nadh Ratio

Diseases associated with mitochondrial DNA (mtDNA) mutations are highly variable in phenotype, in large part because of differences in the percentage of normal and mutant mtDNAs (heteroplasmy) present within the cell. For example, increasing heteroplasmy levels of the mtDNA tRNALeu(UUR) nucleotide (nt) 3243A > G mutation result successively in diabetes, neuromuscular degenerative disease, and perinatal lethality. These phenotypes are associated with differences in mitochondrial function and nuclear DNA (nDNA) gene expression, which are recapitulated in cybrid cell lines with different percentages of m.3243G mutant mtDNAs. Using metabolic tracing, histone mass spectrometry, and NADH fluorescence lifetime imaging microscopy in these cells, we now show that increasing levels of this single mtDNA mutation cause profound changes in the nuclear epigenome. At high heteroplasmy, mitochondrially derived acetyl-CoA levels decrease causing decreased histone H4 acetylation, with glutamine-derived acetyl-CoA compensating when glucose-derived acetyl-CoA is limiting. In contrast, α-ketoglutarate levels increase at midlevel heteroplasmy and are inversely correlated with histone H3 methylation. Inhibition of mitochondrial protein synthesis induces acetylation and methylation changes, and restoration of mitochondrial function reverses these effects. mtDNA heteroplasmy also affects mitochondrial NAD+/NADH ratio, which correlates with nuclear histone acetylation, whereas nuclear NAD+/NADH ratio correlates with changes in nDNA and mtDNA transcription. Thus, mutations in the mtDNA cause distinct metabolic and epigenomic changes at different heteroplasmy levels, potentially explaining transcriptional and phenotypic variability of mitochondrial disease.

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

Current Pharmaceutical Design ◽

10.2174/1381612826666201012164330 ◽

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.

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The Role of Mitochondria in Carcinogenesis

International Journal of Molecular Sciences ◽

10.3390/ijms22105100 ◽

2021 ◽

Vol 22 (10) ◽

pp. 5100

Author(s):

Paulina Kozakiewicz ◽

Ludmiła Grzybowska-Szatkowska ◽

Marzanna Ciesielka ◽

Jolanta Rzymowska

Keyword(s):

Prostate Cancer ◽

Mitochondrial Dna ◽

Nuclear Dna ◽

Dna Polymorphisms ◽

Gene Encoding ◽

Dna Mutations ◽

Nadh Ubiquinone Oxidoreductase ◽

Gene Coi ◽

The Impact

The mitochondria are essential for normal cell functioning. Changes in mitochondrial DNA (mtDNA) may affect the occurrence of some chronic diseases and cancer. This process is complex and not entirely understood. The assignment to a particular mitochondrial haplogroup may be a factor that either contributes to cancer development or reduces its likelihood. Mutations in mtDNA occurring via an increase in reactive oxygen species may favour the occurrence of further changes both in mitochondrial and nuclear DNA. Mitochondrial DNA mutations in postmitotic cells are not inherited, but may play a role both in initiation and progression of cancer. One of the first discovered polymorphisms associated with cancer was in the gene NADH-ubiquinone oxidoreductase chain 3 (mt-ND3) and it was typical of haplogroup N. In prostate cancer, these mutations and polymorphisms involve a gene encoding subunit I of respiratory complex IV cytochrome c oxidase subunit 1 gene (COI). At present, a growing number of studies also address the impact of mtDNA polymorphisms on prognosis in cancer patients. Some of the mitochondrial DNA polymorphisms occur in both chronic disease and cancer, for instance polymorphism G5913A characteristic of prostate cancer and hypertension.

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