Resolving the role of genetic defects and mtDNA copy number in mitochondrial disease and development

Cardiac rupture is a fatal complication after myocardial infarction (MI). However, the detailed mechanism underlying cardiac rupture after MI remains to be fully elucidated. In this study, we investigated the role of mitochondrial DNA (mtDNA) and mitochondria in the pathophysiology of cardiac rupture by analyzing Twinkle helicase overexpression mice (TW mice). Twinkle overexpression increased mtDNA copy number approximately twofold and ameliorated ischemic cardiomyopathy at day 28 after MI. Notably, Twinkle overexpression markedly prevented cardiac rupture and improved post-MI survival, accompanied by the suppression of MMP-2 and MMP-9 in the MI border area at day 5 after MI when cardiac rupture frequently occurs. Additionally, these cardioprotective effects of Twinkle overexpression were abolished in transgenic mice overexpressing mutant Twinkle with an in-frame duplication of amino acids 353–365, which resulted in no increases in mtDNA copy number. Furthermore, although apoptosis and oxidative stress were induced and mitochondria were damaged in the border area, these injuries were improved in TW mice. Further analysis revealed that mitochondrial biogenesis, including mtDNA copy number, transcription, and translation, was severely impaired in the border area at day 5. In contrast, Twinkle overexpression maintained mtDNA copy number and restored the impaired transcription and translation of mtDNA in the border area. These results demonstrated that Twinkle overexpression alleviated impaired mitochondrial biogenesis in the border area through maintained mtDNA copy number and thereby prevented cardiac rupture accompanied by the reduction of apoptosis and oxidative stress, and suppression of MMP activity.

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Role of mitochondria in carcinogenesis.

Acta Biochimica Polonica ◽

10.18388/abp.2014_1829 ◽

2014 ◽

Vol 61 (4) ◽

Cited By ~ 18

Author(s):

Paulina Tokarz ◽

Janusz Blasiak

Keyword(s):

Copy Number ◽

Mtdna Copy Number ◽

Apoptosis Pathway ◽

Mitochondrial Apoptosis Pathway ◽

Mtdna Mutations ◽

Human Cancers ◽

Loop Region ◽

Cancer Cell Survival ◽

Entire Cell

Mitochondria play the central role in supplying cells with ATP and are also the major source of reactive oxygen species (ROS) - molecules of both regulatory and destructive nature. Dysfunction of mitochondrial metabolism and/or morphology have been frequently reported in human cancers. This dysfunction can be associated with mitochondrial DNA (mtDNA) damage, which may be changed into mutations in mtDNA coding sequences, or the displacement-loop region, changes in the mtDNA copy number or mtDNA microsatellite instability. All these features are frequently associated with human cancers. Mutations in mtDNA can disturb the functioning of the ROS-producing organelle and further affect the entire cell which may contribute to genomic instability typical for cancer cells. Although the association between some mtDNA mutations and cancer is well established, the causative relationship between these two features is largely unknown. A hint suggesting the driving role of mtDNA mutations in carcinogenesis comes from the observation of tumor promotion after mtDNA depletion. Mitochondria with damaged DNA may alter signaling of the mitochondrial apoptosis pathway promoting cancer cell survival and conferring resistance to anticancer drugs. This resistance may be underlined by mtDNA copy number depletion. Therefore, mitochondria are considered a promising target in anticancer therapy and several mitochondria-targeting drugs are in preclinical and clinical trials. Some other aspects of mitochondrial structure and functions, including morphology and redox potential, can also be associated with cancer transformation and constitute new anticancer targets. Recently, several studies have disclosed new mechanisms underlying the association between mitochondria and cancer, including the protection of mtDNA by telomerase, suggesting new approaches in mitochondria-oriented anti-cancer therapy.

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Blood cell respiration rates and mtDNA copy number: A promising tool for the diagnosis of mitochondrial disease

Mitochondrion ◽

10.1016/j.mito.2021.09.004 ◽

2021 ◽

Vol 61 ◽

pp. 31-43

Author(s):

Martina Alonso ◽

Cristina Zabala ◽

Santiago Mansilla ◽

Laureana De Brun ◽

Jennyfer Martínez ◽

...

Keyword(s):

Blood Cell ◽

Mitochondrial Disease ◽

Copy Number ◽

Cell Respiration ◽

Mtdna Copy Number ◽

Respiration Rates ◽

Promising Tool

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

Molecular Biology of the Cell ◽

10.1091/mbc.10.10.3345 ◽

1999 ◽

Vol 10 (10) ◽

pp. 3345-3356 ◽

Cited By ~ 54

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.

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Role of the mitochondrial genome in preimplantation development and assisted reproductive technologies

Reproduction Fertility and Development ◽

10.1071/rd04084 ◽

2005 ◽

Vol 17 (2) ◽

pp. 15 ◽

Cited By ~ 48

Author(s):

Lawrence C. Smith ◽

Jacob Thundathil ◽

France Filion

Keyword(s):

Mitochondrial Genome ◽

Copy Number ◽

Cell Function ◽

Assisted Reproductive Technologies ◽

Reproductive Technologies ◽

Domestic Animals ◽

Preimplantation Development ◽

Mtdna Copy Number ◽

Transcription And Replication

Our fascination for mitochondria relates to their origin as symbiotic, semi-independent organisms on which we, as eukaryotic beings, rely nearly exclusively to produce energy for every cell function. Therefore, it is not surprising that these organelles play an essential role in many events during early development and in artificial reproductive technologies (ARTs) applied to humans and domestic animals. However, much needs to be learned about the interactions between the nucleus and the mitochondrial genome (mtDNA), particularly with respect to the control of transcription, replication and segregation during preimplantation. Nuclear-encoded factors that control transcription and replication are expressed during preimplantation development in mice and are followed by mtDNA transcription, but these result in no change in mtDNA copy number. However, in cattle, mtDNA copy number increases during blastocyst expansion and hatching. Nuclear genes influence the mtDNA segregation patterns in heteroplasmic animals. Because many ARTs markedly modify the mtDNA content in embryos, it is essential that their application is preceded by careful experimental scrutiny, using suitable animal models.

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