Nuclear but not mitochondrial genome involvement in human age-related mitochondrial dysfunction. Functional integrity of mitochondrial DNA from aged subjects.

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.

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Mitochondrial DNA Integrity: Role in Health and Disease

Cells ◽

10.3390/cells8020100 ◽

2019 ◽

Vol 8 (2) ◽

pp. 100 ◽

Cited By ~ 26

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.

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

Hearing Research ◽

10.1016/j.heares.2006.06.004 ◽

2007 ◽

Vol 226 (1-2) ◽

pp. 185-193 ◽

Cited By ~ 81

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

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Natural and Artificial Mechanisms of Mitochondrial Genome Elimination

Life ◽

10.3390/life11020076 ◽

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.

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Mitochondria and Hematologic Disorders.

Blood ◽

10.1182/blood.v114.22.sci-3.sci-3 ◽

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.

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

Multiple Sclerosis Journal ◽

10.1177/1352458513490547 ◽

2013 ◽

Vol 19 (14) ◽

pp. 1858-1866 ◽

Cited By ~ 11

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.

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Faculty Opinions recommendation of Age-Related Accumulation of Somatic Mitochondrial DNA Mutations in Adult-Derived Human iPSCs.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.726337601.793525594 ◽

2016 ◽

Author(s):

Robert Casper

Keyword(s):

Mitochondrial Dna ◽

Mitochondrial Dna Mutations ◽

Dna Mutations ◽

Age Related ◽

Human Ipscs

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Role of amyloid β-peptide in the pathogenesis of age-related macular degeneration

BMJ Open Ophthalmology ◽

10.1136/bmjophth-2021-000774 ◽

2021 ◽

Vol 6 (1) ◽

pp. e000774

Author(s):

Minwei Wang ◽

Shiqi Su ◽

Shaoyun Jiang ◽

Xinghuai Sun ◽

Jiantao Wang

Keyword(s):

Mitochondrial Dysfunction ◽

Macular Degeneration ◽

Vision Loss ◽

Cell Structure ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Amyloid Β ◽

Age Related Macular Degeneration ◽

Amyloid Β Peptide ◽

Age Related

Age-related macular degeneration (AMD) is the most common eye disease in elderly patients, which could lead to irreversible vision loss and blindness. Increasing evidence indicates that amyloid β-peptide (Aβ) might be associated with the pathogenesis of AMD. In this review, we would like to summarise the current findings in this field. The literature search was done from 1995 to Feb, 2021 with following keywords, ‘Amyloid β-peptide and age-related macular degeneration’, ‘Inflammation and age-related macular degeneration’, ‘Angiogenesis and age-related macular degeneration’, ‘Actin cytoskeleton and amyloid β-peptide’, ‘Mitochondrial dysfunction and amyloid β-peptide’, ‘Ribosomal dysregulation and amyloid β-peptide’ using search engines Pubmed, Google Scholar and Web of Science. Aβ congregates in subretinal drusen of patients with AMD and participates in the pathogenesis of AMD through enhancing inflammatory activity, inducing mitochondrial dysfunction, altering ribosomal function, regulating the lysosomal pathway, affecting RNA splicing, modulating angiogenesis and modifying cell structure in AMD. The methods targeting Aβ are shown to inhibit inflammatory signalling pathway and restore the function of retinal pigment epithelium cells and photoreceptor cells in the subretinal region. Targeting Aβ may provide a novel therapeutic strategy for AMD.

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Hyperbaric oxygen therapy attenuates D-galactose-induced-age-related cardiac dysfunction through mitigating cardiac mitochondrial dysfunction in pre-diabetic rats

European Heart Journal ◽

10.1093/ehjci/ehaa946.3229 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

C Bo-Htay ◽

T Shwe ◽

S Palee ◽

T Pattarasakulchai ◽

K Shinlapawittayatorn ◽

...

Keyword(s):

Mitochondrial Dysfunction ◽

High Fat Diet ◽

Diabetic Rats ◽

Normal Diet ◽

Lv Function ◽

High Fat ◽

Insulin Resistant ◽

Lv Dysfunction ◽

Age Related ◽

Mitochondrial Functions

Abstract Background D-galactose (D-gal) induced ageing has been shown to exacerbate left ventricular (LV) dysfunction via worsening of apoptosis and mitochondrial dysfunction in the heart of obese rats. Hyperbaric oxygen therapy (HBOT) has been demonstrated to exert anti-inflammatory and anti-apoptotic effects in multiple neurological disorders. However, the cardioprotective effect of HBOT on inflammation, apoptosis, LV and mitochondrial functions in D-gal induced ageing rats in the presence of obese-insulin resistant condition has never been investigated. Purpose We sought to determine the effect of HBOT on inflammation, apoptosis, mitochondrial functions and LV function in pre-diabetic rats with D-gal induced ageing. We hypothesized that HBOT attenuates D-gal induced cardiac mitochondrial dysfunctions and reduces inflammation and apoptosis, leading to improved LV function in pre-diabetic rats. Methods Forty-eight male Wistar rats were fed with either normal diet or high-fat diet for 12 weeks. Then, rats were treated with either vehicle groups (0.9% NSS, subcutaneous injection (SC)) or D-gal groups (150 mg/kg/day, SC) for 8 weeks. At week 21, rats in each group were equally divided into 6 sub-groups: normal diet fed rats treated with vehicle (NDV) sham, normal diet fed rats treated with D-gal (NDDg) sham, high fat diet fed rats treated with D-gal (HFDg) sham, high fat diet fed rats treated with vehicle (HFV) + HBOT, NDDg + HBOT and HFDg + HBOT. Sham treated rats were given normal concentration of O2 (flow rate of 80 L/min, 1 ATA for 60 minutes), whereas HBOT treated rats were subjected to 100% O2 (flow rate of 250 L/min, 2 ATA for 60 minutes), given once daily for 2 weeks. Results Under obese-insulin resistant condition, D-gal-induced ageing aggravated LV dysfunction (Fig 1A) and impaired cardiac mitochondrial function, increased cardiac inflammatory and apoptotic markers (Fig 1B). HBOT markedly reduced cardiac TNF-α level and TUNEL positive apoptotic cells, and improved cardiac mitochondrial function as indicated by decreased mitochondrial ROS production, mitochondrial depolarization and mitochondrial swelling, resulting in the restoration of the normal LV function in HFV and NDDg rats, compared to sham NDDg rats. In addition, in HFDg treated rats, HBOT attenuated cardiac TNF-α level, TUNEL positive apoptotic cells and cardiac mitochondrial dysfunction, compared to sham HFDg rats, leading to improved cardiac function as indicated by increased %LV ejection fraction (LVEF) (Figure 1). Conclusion HBOT efficiently alleviates D-gal-induced-age-related LV dysfunction through mitigating inflammation, apoptosis and mitochondrial dysfunction in pre-diabetic rats. Figure 1 Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): 1. The National Science and Technology Development Agency Thailand, 2. Thailand Research Fund Grants

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Mitochondrial DNA Methylation and Human Diseases

International Journal of Molecular Sciences ◽

10.3390/ijms22094594 ◽

2021 ◽

Vol 22 (9) ◽

pp. 4594

Author(s):

Andrea Stoccoro ◽

Fabio Coppedè

Keyword(s):

Dna Methylation ◽

Mitochondrial Dna ◽

Mitochondrial Genome ◽

Nuclear Dna ◽

Epigenetic Modification ◽

Nuclear Genome ◽

Epigenetic Modifications ◽

Human Diseases ◽

Loop Region ◽

D Loop

Epigenetic modifications of the nuclear genome, including DNA methylation, histone modifications and non-coding RNA post-transcriptional regulation, are increasingly being involved in the pathogenesis of several human diseases. Recent evidence suggests that also epigenetic modifications of the mitochondrial genome could contribute to the etiology of human diseases. In particular, altered methylation and hydroxymethylation levels of mitochondrial DNA (mtDNA) have been found in animal models and in human tissues from patients affected by cancer, obesity, diabetes and cardiovascular and neurodegenerative diseases. Moreover, environmental factors, as well as nuclear DNA genetic variants, have been found to impair mtDNA methylation patterns. Some authors failed to find DNA methylation marks in the mitochondrial genome, suggesting that it is unlikely that this epigenetic modification plays any role in the control of the mitochondrial function. On the other hand, several other studies successfully identified the presence of mtDNA methylation, particularly in the mitochondrial displacement loop (D-loop) region, relating it to changes in both mtDNA gene transcription and mitochondrial replication. Overall, investigations performed until now suggest that methylation and hydroxymethylation marks are present in the mtDNA genome, albeit at lower levels compared to those detectable in nuclear DNA, potentially contributing to the mitochondria impairment underlying several human diseases.

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