scholarly journals The Importance of Mitochondrial DNA in Aging and Cancer

2011 ◽  
Vol 2011 ◽  
pp. 1-9 ◽  
Author(s):  
Claus Desler ◽  
Maiken Lise Marcker ◽  
Keshav K. Singh ◽  
Lene Juel Rasmussen
Keyword(s):  
Mitochondrial Dna ◽  
Mitochondrial Genome ◽  
Mitochondrial Dysfunction ◽  
Premature Aging ◽  
Tumor Initiation ◽  
Pathological Conditions ◽  
Contemporary View ◽  
Age Related ◽  
Mitochondrial Ros ◽  
Altered Regulation

Mitochondrial dysfunction has been implicated in premature aging, age-related diseases, and tumor initiation and progression. Alterations of the mitochondrial genome accumulate both in aging tissue and tumors. This paper describes our contemporary view of mechanisms by which alterations of the mitochondrial genome contributes to the development of age- and tumor-related pathological conditions. The mechanisms described encompass altered production of mitochondrial ROS, altered regulation of the nuclear epigenome, affected initiation of apoptosis, and a limiting effect on the production of ribonucleotides and deoxyribonucleotides.

The origin of intermuscular adipose tissue and its pathophysiological implications

2009 ◽  
Vol 297 (5) ◽  
pp. E987-E998 ◽  
Author(s):  
Roberto Vettor ◽  
Gabriella Milan ◽  
Chiara Franzin ◽  
Marta Sanna ◽  
Paolo De Coppi ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Metabolic Diseases ◽  
High Plasma ◽  
Stem Cell Population ◽  
Phenotypic Switch ◽  
Mesenchymal Progenitors ◽  
Intermuscular Adipose Tissue ◽  
Pathological Conditions ◽  
Age Related ◽  
Mitochondrial Ros

The intermuscular adipose tissue (IMAT) is a depot of adipocytes located between muscle bundles. Several investigations have recently been carried out to define the phenotype, the functional characteristics, and the origin of the adipocytes present in this depot. Among the different mechanisms that could be responsible for the accumulation of fat in this site, the dysdifferentiation of muscle-derived stem cells or other mesenchymal progenitors has been postulated, turning them into cells with an adipocyte phenotype. In particular, muscle satellite cells (SCs), a heterogeneous stem cell population characterized by plasticity and self-renewal that allow muscular growth and regeneration, can acquire features of adipocytes, including the abilities to express adipocyte-specific genes and accumulate lipids. Failure to express the transcription factors that direct mesenchymal precursors into fully differentiated functionally specialized cells may be responsible for their phenotypic switch into the adipogenic lineage. We proved that human SCs also possess a clear adipogenic potential that could explain the presence of mature adipocytes within skeletal muscle. This occurs under some pathological conditions (i.e., primary myodystrophies, obesity, hyperglycemia, high plasma free fatty acids, hypoxia, etc.) or as a consequence of thiazolidinedione treatment or simply because of a sedentary lifestyle or during aging. Several pathways and factors (PPARs, WNT growth factors, myokines, GEF-GAP-Rho, p66shc, mitochondrial ROS production, PKCβ) could be implicated in the adipogenic conversion of SCs. The understanding of the molecular pathways that regulate muscle-to-fat conversion and SC behavior could explain the increase in IMAT depots that characterize many metabolic diseases and age-related sarcopenia.

scholarly journals Mitochondrial DNA Integrity: Role in Health and Disease

Cells ◽  
2019 ◽  
Vol 8 (2) ◽  
pp. 100 ◽  
Author(s):  
Priyanka Sharma ◽  
Harini Sampath
Keyword(s):  
Mitochondrial Dna ◽  
Mitochondrial Genome ◽  
Genome Stability ◽  
Dna Lesions ◽  
Genome Integrity ◽  
Dna Integrity ◽  
Age Related ◽  
Genome Damage ◽  
Health And Disease ◽  
Mitochondrial Genome Stability

As the primary cellular location for respiration and energy production, mitochondria serve in a critical capacity to the cell. Yet, by virtue of this very function of respiration, mitochondria are subject to constant oxidative stress that can damage one of the unique features of this organelle, its distinct genome. Damage to mitochondrial DNA (mtDNA) and loss of mitochondrial genome integrity is increasingly understood to play a role in the development of both severe early-onset maladies and chronic age-related diseases. In this article, we review the processes by which mtDNA integrity is maintained, with an emphasis on the repair of oxidative DNA lesions, and the cellular consequences of diminished mitochondrial genome stability.

Role of mitochondrial dysfunction and mitochondrial DNA mutations in age-related hearing loss

2007 ◽  
Vol 226 (1-2) ◽  
pp. 185-193 ◽  
Author(s):  
Tatsuya Yamasoba ◽  
Shinichi Someya ◽  
Chikako Yamada ◽  
Richard Weindruch ◽  
Tomas A. Prolla ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Mitochondrial Dna ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Dna Mutations ◽  
Dna Mutations ◽  
Age Related ◽  
Age Related Hearing Loss

scholarly journals Natural and Artificial Mechanisms of Mitochondrial Genome Elimination

Life ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 76
Author(s):  
Elvira G. Zakirova ◽  
Vladimir V. Muzyka ◽  
Ilya O. Mazunin ◽  
Konstantin E. Orishchenko
Keyword(s):  
Mitochondrial Dna ◽  
Mitochondrial Genome ◽  
Mitochondrial Dysfunction ◽  
Genetic Drift ◽  
Genetic Regulation ◽  
Somatic Cells ◽  
Present Knowledge ◽  
Mammalian Development ◽  
Current Review ◽  
Female Germline

The generally accepted theory of the genetic drift of mitochondrial alleles during mammalian ontogenesis is based on the presence of a selective bottleneck in the female germline. However, there is a variety of different theories on the pathways of genetic regulation of mitochondrial DNA (mtDNA) dynamics in oogenesis and adult somatic cells. The current review summarizes present knowledge on the natural mechanisms of mitochondrial genome elimination during mammalian development. We also discuss the variety of existing and developing methodologies for artificial manipulation of the mtDNA heteroplasmy level. Understanding of the basics of mtDNA dynamics will shed the light on the pathogenesis and potential therapies of human diseases associated with mitochondrial dysfunction.

Mitochondria and Hematologic Disorders.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. SCI-3-SCI-3
Author(s):  
Jeff S. Friedman
Keyword(s):  
Mitochondrial Dna ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Biogenesis ◽  
Conflicts Of Interest ◽  
Single Cells ◽  
Disease Process ◽  
Dna Lesions ◽  
Special Relationship ◽  
Hematopoietic Stem ◽  
Age Related

Abstract Abstract SCI-3 Mitochondria have a special relationship with the erythroid lineage. Although RBC are devoid of mitochondria, during RBC development the mitochondria is the site of multiple steps in heme biosynthesis, and is essential for proper utilization of iron. As evidence of this special relationship, multiple mutations in both mitochondrial DNA (hereditary and acquired) and in nuclear genes encoding mitochondrial localized proteins (hereditary) result in sideroblastic anemia—where the hallmark pathologic lesion is intramitochondrial iron accumulation in erythroid progenitors. The erythroid-lineage specific readout of these mitochondrial genetic lesions raises the possibility that mitochondrial dysfunction is a contributor to anemia in other contexts as well. In this view, red cell development can be considered an early warning system for mitochondrial dysfunction in hematopoiesis. A focus of our laboratory is to investigate how increased mitochondrial-derived reactive oxygen species affect hematopoietic development. Gene expression and proteomic analyses of erythroblasts demonstrate that mitochondrial biogenesis during erythroid development is inhibited by oxidant stress. Transcriptional control of mitochondrial biogenesis in erythroid cells involves induction of the distinct transcriptional coactivator PRC1—perhaps helping to explain the erythroid specificity of phenotypes noted above. As has been elegantly demonstrated by Wallace and others, mitochondrial dysfunction is an important determinant of age-related decline in functional capacity of many tissues. This decline in function is accompanied by an increase in mitochondrial DNA mutations—both point mutations and deletions found primarily in post-mitotic cells. Modeling of this process through creation of mice with an error prone mtDNA polymerase accelerates the appearance of age-related tissue changes—including the development of anemia. Transplantation of murine hematopoietic stem cells harboring a large deletion of mtDNA also leads to anemia in reconstituted animals. Are these findings relevant for age-related hematologic abnormalities in people—and if so, for what disorders? There is considerable epidemiologic evidence indicating an increase in the frequency of anemia in the elderly, peaking at a prevalence of greater than 20% for individuals in their 80's. Approximately 1/3 of these elderly anemic cases are idiopathic—that is, no underlying disease process is identified. In studying this group with idiopathic anemia, we have investigated a number of hypotheses including the possibility of mitochondrial dysfunction. To date we have found altered mitochondrial DNA content and a higher mutation frequency in mtDNA isolated from peripheral blood cells when comparing anemic versus age/sex matched controls. However, these studies are correlative, and do not prove causality. Proving a direct role for specific acquired mitochondrial DNA lesions in development of anemia, myelodysplasia or hematologic malignancy remains a technical challenge because of the difficulty in introducing specific mutant mtDNA's into relevant cells or tissues. The development of more facile methods for evaluation of mitochondria in few or even single cells promises to expand our understanding of how mitochondrial functional changes impact diverse hematopoietic cells, in addition to the erythroid lineage effects highlighted above. Disclosures No relevant conflicts of interest to declare.

scholarly journals No excess of mitochondrial DNA deletions within muscle in progressive multiple sclerosis

2013 ◽  
Vol 19 (14) ◽  
pp. 1858-1866 ◽  
Author(s):  
Graham R Campbell ◽  
Amy K Reeve ◽  
Iryna Ziabreva ◽  
Richard Reynolds ◽  
Doug M Turnbull ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Mitochondrial Dna ◽  
Mitochondrial Dysfunction ◽  
Chain Complex ◽  
Muscle Fibres ◽  
Mitochondrial Respiratory Chain Complex ◽  
Respiratory Enzyme ◽  
Mtdna Deletions ◽  
Age Related ◽  
Enzyme Deficient

Background: Mitochondrial dysfunction is an established feature of multiple sclerosis (MS). We recently described high levels of mitochondrial DNA (mtDNA) deletions within respiratory enzyme-deficient (lacking mitochondrial respiratory chain complex IV with intact complex II) neurons and choroid plexus epithelial cells in progressive MS. Objectives: The objective of this paper is to determine whether respiratory enzyme deficiency and mtDNA deletions in MS were in excess of age-related changes within muscle, which, like neurons, are post-mitotic cells that frequently harbour mtDNA deletions with ageing and in disease. Methods: In progressive MS cases ( n=17), known to harbour an excess of mtDNA deletions in the central nervous system (CNS), and controls ( n=15), we studied muscle (paraspinal) and explored mitochondria in single fibres. Histochemistry, immunohistochemistry, laser microdissection, real-time polymerase chain reaction (PCR), long-range PCR and sequencing were used to resolve the single muscle fibres. Results: The percentage of respiratory enzyme-deficient muscle fibres, mtDNA deletion level and percentage of muscle fibres harbouring high levels of mtDNA deletions were not significantly different in MS compared with controls. Conclusion: Our findings do not provide support to the existence of a diffuse mitochondrial abnormality involving multiple systems in MS. Understanding the cause(s) of the CNS mitochondrial dysfunction in progressive MS remains a research priority.

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.

The Role of Glyoxalase in Glycation and Carbonyl Stress Induced Metabolic Disorders

2020 ◽  
Vol 21 (9) ◽  
pp. 846-859
Author(s):  
Mohd Saeed ◽  
Mohd Adnan Kausar ◽  
Rajeev Singh ◽  
Arif J. Siddiqui ◽  
Asma Akhter
Keyword(s):  
Protein Misfolding ◽  
Covalent Binding ◽  
Critical Role ◽  
Enzymatic Reaction ◽  
Treatment Strategies ◽  
Bioactive Molecules ◽  
Carbonyl Stress ◽  
Defense System ◽  
Pathological Conditions ◽  
Age Related

Glycation refers to the covalent binding of sugar molecules to macromolecules, such as DNA, proteins, and lipids in a non-enzymatic reaction, resulting in the formation of irreversibly bound products known as advanced glycation end products (AGEs). AGEs are synthesized in high amounts both in pathological conditions, such as diabetes and under physiological conditions resulting in aging. The body’s anti-glycation defense mechanisms play a critical role in removing glycated products. However, if this defense system fails, AGEs start accumulating, which results in pathological conditions. Studies have been shown that increased accumulation of AGEs acts as key mediators in multiple diseases, such as diabetes, obesity, arthritis, cancer, atherosclerosis, decreased skin elasticity, male erectile dysfunction, pulmonary fibrosis, aging, and Alzheimer’s disease. Furthermore, glycation of nucleotides, proteins, and phospholipids by α-oxoaldehyde metabolites, such as glyoxal (GO) and methylglyoxal (MGO), causes potential damage to the genome, proteome, and lipidome. Glyoxalase-1 (GLO-1) acts as a part of the anti-glycation defense system by carrying out detoxification of GO and MGO. It has been demonstrated that GLO-1 protects dicarbonyl modifications of the proteome and lipidome, thereby impeding the cell signaling and affecting age-related diseases. Its relationship with detoxification and anti-glycation defense is well established. Glycation of proteins by MGO and GO results in protein misfolding, thereby affecting their structure and function. These findings provide evidence for the rationale that the functional modulation of the GLO pathway could be used as a potential therapeutic target. In the present review, we summarized the newly emerged literature on the GLO pathway, including enzymes regulating the process. In addition, we described small bioactive molecules with the potential to modulate the GLO pathway, thereby providing a basis for the development of new treatment strategies against age-related complications.

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