Deletion-Mutant mtDNA Increases in Somatic Tissues but Decreases in Female Germ Cells With Age

Sato, Ayumu; Nakada, Kazuto; Shitara, Hiroshi; Kasahara, Atsuko; Yonekawa, Hiromichi; Hayashi, Jun‐Ichi

doi:10.1534/genetics.107.081026

Cited by 46 publications

(62 citation statements)

References 35 publications

(50 reference statements)

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“…Rather, segregation must occur later in female germ cell development without reduction in mtDNA copy number, presumably because of differential replication of mtDNAs during oocyte maturation. Consistent with this conclusion, they point out that mouse models heteroplasmic for highly deleterious mtDNA mutations including an mtDNA 4696-nt deletion (Sato et al 2007) and an ND6 frameshift mutation (Fan et al 2008) produced pups with lower percentages of mutant mtDNAs in successive litters. If the mtDNA variance were entirely determined by segregation and/or selection early in female germline development, then all litters should be generated from oocytes with the same distribution of heteroplasmy levels.…”

Section: Germline Segregation Of Mtdna Heteroplasmymentioning

confidence: 64%

Mitochondrial DNA Genetics and the Heteroplasmy Conundrum in Evolution and Disease

Wallace

Chalkia

2013

Cold Spring Harbor Perspectives in Biology

559

565

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The unorthodox genetics of the mtDNA is providing new perspectives on the etiology of the common "complex" diseases. The maternally inherited mtDNA codes for essential energy genes, is present in thousands of copies per cell, and has a very high mutation rate. New mtDNA mutations arise among thousands of other mtDNAs. The mechanisms by which these "heteroplasmic" mtDNA mutations come to predominate in the female germline and somatic tissues is poorly understood, but essential for understanding the clinical variability of a range of diseases. Maternal inheritance and heteroplasmy also pose major challengers for the diagnosis and prevention of mtDNA disease. THE GENETIC CHALLENGES OF mtDNA DISEASES

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Section: Germline Segregation Of Mtdna Heteroplasmymentioning

confidence: 64%

Mitochondrial DNA Genetics and the Heteroplasmy Conundrum in Evolution and Disease

Wallace

Chalkia

2013

Cold Spring Harbor Perspectives in Biology

559

565

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“…On the other hand, a variety of tRNA mutations were transmitted through the maternal lineage (Stewart et al 2008). Studies of mice containing the 4696-bp deletion have also shown a decrease in the levels of deleted mtDNA in female germ cells and their offspring, although the level of deleted mtDNA remained constant or increased in somatic tissues with age (Sato et al 2007). …”

Section: Introduction Of Mtdna Into the Mousementioning

confidence: 99%

The pathophysiology of mitochondrial disease as modeled in the mouse

Wallace¹,

Fan²

2009

Genes Dev.

184

150

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It is now clear that mitochondrial defects are associated with a plethora of clinical phenotypes in man and mouse. This is the result of the mitochondria's central role in energy production, reactive oxygen species (ROS) biology, and apoptosis, and because the mitochondrial genome consists of roughly 1500 genes distributed across the maternal mitochondrial DNA (mtDNA) and the Mendelian nuclear DNA (nDNA). While numerous pathogenic mutations in both mtDNA and nDNA mitochondrial genes have been identified in the past 21 years, the causal role of mitochondrial dysfunction in the common metabolic and degenerative diseases, cancer, and aging is still debated. However, the development of mice harboring mitochondrial gene mutations is permitting demonstration of the direct cause-and-effect relationship between mitochondrial dysfunction and disease. Mutations in nDNA-encoded mitochondrial genes involved in energy metabolism, antioxidant defenses, apoptosis via the mitochondrial permeability transition pore (mtPTP), mitochondrial fusion, and mtDNA biogenesis have already demonstrated the phenotypic importance of mitochondrial defects. These studies are being expanded by the recent development of procedures for introducing mtDNA mutations into the mouse. These studies are providing direct proof that mtDNA mutations are sufficient by themselves to generate major clinical phenotypes. As more different mtDNA types and mtDNA gene mutations are introduced into various mouse nDNA backgrounds, the potential functional role of mtDNA variation in permitting humans and mammals to adapt to different environments and in determining their predisposition to a wide array of diseases should be definitively demonstrated.

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“…3) [16,36]. In the case of mito-mice∆ carrying more than 70% ∆mtDNA at birth, the mitomice∆ showed mitochondrial respiration defects and disease phenotypes and consequently died at around 6 months after birth [16,17,[26][27][28][29]41].…”

mentioning

confidence: 99%

“…In the case of mito-mice∆, however, ∆mtDNA is inherited by progeny until at least the third pregnancy, since the amount of ∆mtDNA in eggs decreases with the aging of female mito-mice∆ [36]. In addition, it is difficult to obtain a large population of mito-mice∆ with the same ∆mtDNA load.…”

mentioning

confidence: 99%

Transmitochondrial Mice as Models for Mitochondrial DNA-Based Diseases

Nakada

Hayashi

2011

Exp. Anim.

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Mitochondrial genome (mtDNA) mutations and the resultant mitochondrial respiratory abnormalities are associated with a wide variety of disorders, such as mitochondrial diseases, neurodegenerative diseases, diabetes, and cancer, as well as aging. Generation of model animals carrying mutant mtDNAs is important for understanding the pathophysiological mechanisms of the mtDNA-based diseases. We have succeeded in generating three kinds of mice with pathogenic mutant mtDNAs, named "mito-mice," by the introduction of mitochondria carrying pathogenic mutant mtDNAs into mouse zygotes and mouse embryonic stem (ES) cells. In the case of mito-mice possessing the heteroplasmic state of wild-type mtDNA and pathogenic mtDNA with a large-scale deletion (∆mtDNA, mito-mice∆), a high load of ∆mtDNA induced mitochondrial respiration defects in various tissues, resulting in mitochondrial disease phenotypes, such as low body weight, lactic acidosis, ischemia, myopathy, heart block, deafness, male infertility, long-term memory defects, and renal failure. In this review, we summarize generation and clinical phenotypes of three types of mito-mice and we introduce several treatment trials for mitochondrial diseases using mito-mice∆.

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Deletion-Mutant mtDNA Increases in Somatic Tissues but Decreases in Female Germ Cells With Age

Abstract: The proportions of mutant and wild-type mtDNA are crucial in determining the severity of mitochondrial diseases. It has been generally considered that deletion-mutant mtDNA has replication advantages and accumulates with time.

Cited by 46 publications

References 35 publications

Mitochondrial DNA Genetics and the Heteroplasmy Conundrum in Evolution and Disease

Mitochondrial DNA Genetics and the Heteroplasmy Conundrum in Evolution and Disease

The pathophysiology of mitochondrial disease as modeled in the mouse

Transmitochondrial Mice as Models for Mitochondrial DNA-Based Diseases

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