scholarly journals The Complicated Nature of Somatic mtDNA Mutations in Aging

2022 ◽  
Vol 2 ◽  
Author(s):  
Monica Sanchez-Contreras ◽  
Scott R. Kennedy
Keyword(s):  
Energy Production ◽  
Somatic Mutations ◽  
De Novo ◽  
The Elderly ◽  
Exact Role ◽  
Mtdna Mutations ◽  
Age Related ◽  
Transport Chain ◽  
Considerable Debate ◽  
Complicated Nature

Mitochondria are the main source of energy used to maintain cellular homeostasis. This aspect of mitochondrial biology underlies their putative role in age-associated tissue dysfunction. Proper functioning of the electron transport chain (ETC), which is partially encoded by the extra-nuclear mitochondrial genome (mtDNA), is key to maintaining this energy production. The acquisition of de novo somatic mutations that interrupt the function of the ETC have long been associated with aging and common diseases of the elderly. Yet, despite over 30 years of study, the exact role(s) mtDNA mutations play in driving aging and its associated pathologies remains under considerable debate. Furthermore, even fundamental aspects of age-related mtDNA mutagenesis, such as when mutations arise during aging, where and how often they occur across tissues, and the specific mechanisms that give rise to them, remain poorly understood. In this review, we address the current understanding of the somatic mtDNA mutations, with an emphasis of when, where, and how these mutations arise during aging. Additionally, we highlight current limitations in our knowledge and critically evaluate the controversies stemming from these limitations. Lastly, we highlight new and emerging technologies that offer potential ways forward in increasing our understanding of somatic mtDNA mutagenesis in the aging process.

scholarly journals Altered basal lipid metabolism underlies the functional impairment of naive CD8+ T cells in elderly humans

2020 ◽  
Author(s):  
Francesco Nicoli ◽  
Mariela P. Cabral-Piccin ◽  
Laura Papagno ◽  
Eleonora Gallerani ◽  
Victor Folcher ◽  
...  
Keyword(s):  
T Cells ◽  
Lipid Metabolism ◽  
T Cell ◽  
De Novo ◽  
The Elderly ◽  
Influenza Viruses ◽  
Emerging Pathogens ◽  
Cell Compartment ◽  
Age Related

ABSTRACTAging is associated with functional deficits in the naive T cell compartment, which compromise the generation of de novo immune responses against previously unencountered antigens. The mechanisms that underlie this phenomenon have nonetheless remained unclear. We identified an age-related link between altered basal lipid metabolism and impaired antigen responsiveness in the naive CD8+ T cell compartment. These abnormalities were associated with an enhanced susceptibility to activation-induced apoptosis and could be recapitulated in vitro by exposure to the homeostatic cytokine interleukin (IL)-7. Importantly, reversal of the bioenergetic anomalies with lipid-altering drugs, such as rosiglitazone, almost completely restored the functional capabilities of naive CD8+ T cells. Interventions that favor lipid catabolism may therefore find utility as adjunctive therapies in the elderly to promote vaccine-induced immunity against emerging pathogens, such as seasonal influenza viruses and SARS-CoV-2.

scholarly journals Mitochondrial mutational spectrum in mammals is sensitive to cellular and organismal longevity by means of A>G transitions

2019 ◽  
Author(s):  
A. G. Mikhaylova ◽  
A. A. Mikhailova ◽  
K. Ushakova ◽  
E.O. Tretiakov ◽  
A. Yurchenko ◽  
...  
Keyword(s):  
Energy Production ◽  
De Novo ◽  
Mammalian Species ◽  
Nuclear Genome ◽  
Mutational Signatures ◽  
Mutational Spectra ◽  
Mtdna Mutations ◽  
Mutational Spectrum ◽  
Heavy Strand ◽  
Different Tissues

AbstractMutational spectrum of the mitochondrial genome (mtDNA) does not resemble any of the known mutational signatures of the nuclear genome and variation in mtDNA mutational spectra between different tissues and organisms is still incomprehensible. Since mitochondria is tightly involved in energy production, we expect that mtDNA mutational spectra can reflect the level of cellular aerobic metabolism, which varies in different tissues. Analyzing a collection of somatic mtDNA mutations from human cancers, de novo mtDNA germline mutations from the human mother-offspring pairs, as well as mtDNA substitutions in hundreds of mammalian species, we observed that the frequency of AH>GH (heavy strand notation) substitutions is positively correlated with cellular and organismal longevity. For example, epithelium, oocytes of young mothers and mice have decreased AH>GH frequencies. We propose that AH>GH is a marker of cellular and organismal age, which is driven by oxidative damage of the single-stranded mtDNA during replication.Graphical abstractwhy melanoma is similar to a mouse and glioblastome resembles an elephant?

scholarly journals A replication-linked mutational gradient drives somatic mutation accumulation and influences germline polymorphisms and genome composition in mitochondrial DNA

2021 ◽  
Author(s):  
Monica Sanchez-Contreras ◽  
Mariya T Sweetwyne ◽  
Brendan F Kohrn ◽  
Kristine A Tsantilas ◽  
Michael J Hipp ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Somatic Mutations ◽  
De Novo ◽  
Primary Source ◽  
Regulatory Elements ◽  
Genome Replication ◽  
Nucleotide Polymorphisms ◽  
De Novo Mutations ◽  
Genome Composition ◽  
Mtdna Mutations

Abstract Mutations in mitochondrial DNA (mtDNA) cause maternally inherited diseases, while somatic mutations are linked to common diseases of aging. Although mtDNA mutations impact health, the processes that give rise to them are under considerable debate. To investigate the mechanism by which de novo mutations arise, we analyzed the distribution of naturally occurring somatic mutations across the mouse and human mtDNA obtained by Duplex Sequencing. We observe distinct mutational gradients in G→A and T→C transitions delimited by the light-strand origin and the mitochondrial Control Region (mCR). The gradient increases unequally across the mtDNA with age and is lost in the absence of DNA polymerase γ proofreading activity. In addition, high-resolution analysis of the mCR shows that important regulatory elements exhibit considerable variability in mutation frequency, consistent with them being mutational ‘hot-spots’ or ‘cold-spots’. Collectively, these patterns support genome replication via a deamination prone asymmetric strand-displacement mechanism as the fundamental driver of mutagenesis in mammalian DNA. Moreover, the distribution of mtDNA single nucleotide polymorphisms in humans and the distribution of bases in the mtDNA across vertebrate species mirror this gradient, indicating that replication-linked mutations are likely the primary source of inherited polymorphisms that, over evolutionary timescales, influences genome composition during speciation.

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 Aberrant mitochondrial function in ageing and cancer

2019 ◽  
Vol 21 (4) ◽  
pp. 445-459 ◽  
Author(s):  
Julia C. Whitehall ◽  
Laura C. Greaves
Keyword(s):  
Risk Factor ◽  
Cancer Cells ◽  
Tumour Growth ◽  
Somatic Mutations ◽  
Mitochondrial Metabolism ◽  
Cancer Development ◽  
Mtdna Mutations ◽  
Age Related ◽  
Mitochondrial Functions ◽  
Cancer Types

AbstractAlterations in mitochondrial metabolism have been described as one of the major hallmarks of both ageing cells and cancer. Age is the biggest risk factor for the development of a significant number of cancer types and this therefore raises the question of whether there is a link between age-related mitochondrial dysfunction and the advantageous changes in mitochondrial metabolism prevalent in cancer cells. A common underlying feature of both ageing and cancer cells is the presence of somatic mutations of the mitochondrial genome (mtDNA) which we postulate may drive compensatory alterations in mitochondrial metabolism that are advantageous for tumour growth. In this review, we discuss basic mitochondrial functions, mechanisms of mtDNA mutagenesis and their metabolic consequences, and review the evidence for and against a role for mtDNA mutations in cancer development.

scholarly journals Features of Retinal Neurogenesis as a Key Factor of Age-Related Neurodegeneration: Myth or Reality?

2021 ◽  
Vol 22 (14) ◽  
pp. 7373
Author(s):  
Darya V. Telegina ◽  
Oyuna S. Kozhevnikova ◽  
Anna K. Antonenko ◽  
Nataliya G. Kolosova
Keyword(s):  
De Novo ◽  
The Elderly ◽  
Developed Countries ◽  
Pathological Process ◽  
Age Related Macular Degeneration ◽  
Long Term Effects ◽  
Functional Changes ◽  
Age Related ◽  
Functional Features ◽  
Retinal Neurogenesis

Age-related macular degeneration (AMD) is a complex multifactorial neurodegenerative disease that constitutes the most common cause of irreversible blindness in the elderly in the developed countries. Incomplete knowledge about its pathogenesis prevents the search for effective methods of prevention and treatment of AMD, primarily of its “dry” type which is by far the most common (90% of all AMD cases). In the recent years, AMD has become “younger”: late stages of the disease are now detected in relatively young people. It is known that AMD pathogenesis—according to the age-related structural and functional changes in the retina—is linked with inflammation, hypoxia, oxidative stress, mitochondrial dysfunction, and an impairment of neurotrophic support, but the mechanisms that trigger the conversion of normal age-related changes to the pathological process as well as the reason for early AMD development remain unclear. In the adult mammalian retina, de novo neurogenesis is very limited. Therefore, the structural and functional features that arise during its maturation and formation can exert long-term effects on further ontogenesis of this tissue. The aim of this review was to discuss possible contributions of the changes/disturbances in retinal neurogenesis to the early development of AMD.

scholarly journals Features of Retinal Neurogenesis as a Key Factor of Age-Related Neurodegeneration: Myth or Reality?

2021 ◽  
Author(s):  
Darya Telegina ◽  
Oyuna Kozhevnikova ◽  
Anna Antonenko ◽  
Nataliya Kolosova
Keyword(s):  
De Novo ◽  
The Elderly ◽  
Developed Countries ◽  
Pathological Process ◽  
Age Related Macular Degeneration ◽  
Long Term Effects ◽  
Functional Changes ◽  
Age Related ◽  
Functional Features ◽  
Retinal Neurogenesis

Age-related macular degeneration (AMD) is a complex, multifactorial neurodegenerative disease that constitutes the most common cause of irreversible blindness in the elderly in developed countries. Incomplete knowledge about its pathogenesis prevents the search for effective methods of prevention and treatment of AMD, primarily its “dry” type, which is by far the most common (90% of all AMD cases). In recent years, AMD became younger: late stages of the disease are now detected in relatively young people. It is known that AMD pathogenesis—according to the age-related structural and functional changes in the retina—is linked with inflammation, hypoxia, oxidative stress, mitochondrial dysfunction, and an impairment of neurotrophic support, but the mechanisms that trigger the conversion of normal age-related changes to the pathological process as well as the reason for early AMD development remain unclear. In the adult mammalian retina, de novo neurogenesis is very limited. Therefore, the structural and functional features that arise during its maturation and formation can exert long-term effects on further ontogenesis of this tissue. The aim of this review is to discuss possible contributions of the changes/disturbances in retinal neurogenesis to the early development of AMD.

scholarly journals Extensive tissue-related and allele-related mtDNA heteroplasmy suggests positive selection for somatic mutations

2015 ◽  
Vol 112 (8) ◽  
pp. 2491-2496 ◽  
Author(s):  
Mingkun Li ◽  
Roland Schröder ◽  
Shengyu Ni ◽  
Burkhard Madea ◽  
Mark Stoneking
Keyword(s):  
Positive Selection ◽  
Protein Function ◽  
Somatic Mutations ◽  
Significant Excess ◽  
High Frequencies ◽  
Mtdna Mutations ◽  
Age Related ◽  
Selection For ◽  
Different Tissues ◽  
Complete Mtdna

Heteroplasmy in human mtDNA may play a role in cancer, other diseases, and aging, but patterns of heteroplasmy variation across different tissues have not been thoroughly investigated. Here, we analyzed complete mtDNA genome sequences at ∼3,500× average coverage from each of 12 tissues obtained at autopsy from each of 152 individuals. We identified 4,577 heteroplasmies (with an alternative allele frequency of at least 0.5%) at 393 positions across the mtDNA genome. Surprisingly, different nucleotide positions (nps) exhibit high frequencies of heteroplasmy in different tissues, and, moreover, heteroplasmy is strongly dependent on the specific consensus allele at an np. All of these tissue-related and allele-related heteroplasmies show a significant age-related accumulation, suggesting positive selection for specific alleles at specific positions in specific tissues. We also find a highly significant excess of liver-specific heteroplasmies involving nonsynonymous changes, most of which are predicted to have an impact on protein function. This apparent positive selection for reduced mitochondrial function in the liver may reflect selection to decrease damaging byproducts of liver mitochondrial metabolism (i.e., “survival of the slowest”). Overall, our results provide compelling evidence for positive selection acting on some somatic mtDNA mutations.

scholarly journals Thymic rejuvenation via induced thymic epithelial cells (iTECs) from FOXN1-overexpressing fibroblasts to counteract inflammaging

2020 ◽  
Author(s):  
Jiyoung Oh ◽  
Weikan Wang ◽  
Rachel Thomas ◽  
Dong-Ming Su
Keyword(s):  
T Cell ◽  
Epithelial Cells ◽  
Negative Selection ◽  
De Novo ◽  
The Elderly ◽  
Thymic Epithelial Cells ◽  
Thymic Involution ◽  
Embryonic Fibroblasts ◽  
Central Tolerance ◽  
Age Related

AbstractAge-associated systemic, chronic, sterile inflammatory condition (inflammaging) is partially attributed to increased self (auto)-reactivity, resulting from disruption of central tolerance in the aged, involuted thymus. Age-related thymic involution causally results from gradually declined expression of the transcription factor forkhead box N1 (FOXN1) in thymic epithelial cells (TECs), while exogenous FOXN1 in TECs can significantly rescue age-related thymic involution. Given the findings that induced TECs (iTECs) from FOXN1-overexpressing embryonic fibroblasts can generate an ectopic de novo thymus under the kidney capsule and intra-thymically injected natural young TECs can lead to middle-aged thymus regrowth, we sought to expand upon these two findings by applying them as a novel thymic rejuvenation strategy with two types of promoter-driven (Rosa26CreERT and FoxN1Cre) Cre-mediated iTECs. We engrafted iTECs, rather than natural young TECs, directly into the aged thymus and/or peri-thymus and found a significantly rejuvenated architecture and function in the native aged murine thymus. The engrafted iTECs drove regrowth of the aged thymus in both male and female mice, showing not only increased thymopoiesis, but also reinforcement of thymocyte negative selection, thereby, reducing senescent T cells and auto-reactive T cell-mediated inflammaging phenotypes in old mice. Therefore, this is a promising thymic rejuvenation strategy with preclinical significance, which can potentially rescue declined thymopoiesis and impaired negative selection to significantly, albeit partially, restore the defective central tolerance and reduce subclinical chronic inflammatory symptoms in the elderly.Graphical AbstractA novel rejuvenation strategy via the FOXN1-TEC axis using induced two types of FOXN1-overexpressing embryonic fibroblasts (termed iTECs) by intrathymic injection is able to counteract age-related thymic involution, which rescued negative selection, thereby, reducing peripheral T cell-associated inflammaging conditions.

scholarly journals A mutational gradient drives somatic mutation accumulation in mitochondrial DNA and influences germline polymorphisms and genome composition

2021 ◽  
Author(s):  
Monica Sanchez-Contreras ◽  
Mariya T Sweetwyne ◽  
Brendan F Kohrn ◽  
Kristine A Tsantilas ◽  
Jeanne Fredrickson ◽  
...  
Keyword(s):  
Somatic Mutation ◽  
Control Region ◽  
Somatic Mutations ◽  
De Novo ◽  
Mutation Accumulation ◽  
De Novo Mutations ◽  
Genome Composition ◽  
Mtdna Mutations ◽  
High Resolution Analysis ◽  
Mtdna Replication

Background: Mutations in the mitochondrial genome (mtDNA) can cause devastating maternally inherited diseases, while the accumulation of somatic mtDNA mutations is linked to common diseases of aging. Although mtDNA mutations impact human health, the process(es) that give rise to these mutations are unclear and are under considerable debate. We analyzed the distribution of naturally occurring somatic mutations across the mouse and human mtDNA obtained by Duplex Sequencing to provide clues to the mechanism by which de novo mutations arise as well as how the genome is replicated. Results: We observe two distinct mutational gradients in G→A and T→C transitions, but not their complements, that are delimited by the light-strand origin and the control region (CR). The gradients increase with age and are lost in the absence of DNA polymerase γ proofreading activity. A nearly identical pattern is present in human mtDNA somatic mutations. The distribution of mtDNA SNPs in the human population and genome base composition across >3,000 vertebrate species mirror this gradient pattern, pointing to evolutionary conservation of this phenomenon. Lastly, high-resolution analysis of the mtDNA control region highlights mutational hot-spots and cold-spots that strongly align with important regulatory regions. Conclusions: Collectively, these patterns support an asymmetric strand-displacement mechanism with key regulatory structures in the CR and argue against alternative replication models. The mutational gradient is a fundamental consequence of mtDNA replication that drives somatic mutation accumulation and influences inherited polymorphisms and, over evolutionary timescales, genome composition.

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