Accumulation of pathogenic ΔmtDNA induced deafness but not diabetic phenotypes in mito-mice

Nakada, Kazuto; Sato, Ayumu; Sone, Hideyuki; Kasahara, Atsuko; Ikeda, Katsuhisa; Kagawa, Yasuo; Yonekawa, Hiromichi; Hayashi, Jun‐Ichi

doi:10.1016/j.bbrc.2004.08.073

Cited by 40 publications

(41 citation statements)

References 35 publications

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“…Our previous study (19) also showed that young mito-miceND6 M (3-mo-old males) have slight lactic acidosis, a common phenotype in humans with mitochondrial diseases (1, 2) and in mito-mice with other pathogenic mtDNA mutations (20)(21)(22). Using aged mitomiceND6 M (21-mo-old males), this study reexamined blood lactate levels.…”

Section: Resultsmentioning

confidence: 83%

Specific mitochondrial DNA mutation in mice regulates diabetes and lymphoma development

Hashizume

Shimizu

Yokota

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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It has been hypothesized that respiration defects caused by accumulation of pathogenic mitochondrial DNA (mtDNA) mutations and the resultant overproduction of reactive oxygen species (ROS) or lactates are responsible for aging and age-associated disorders, including diabetes and tumor development. However, there is no direct evidence to prove the involvement of mtDNA mutations in these processes, because it is difficult to exclude the possible involvement of nuclear DNA mutations. Our previous studies resolved this issue by using an mtDNA exchange technology and showed that a G13997A mtDNA mutation found in mouse tumor cells induces metastasis via ROS overproduction. Here, using transmitochondrial mice (mitomice), which we had generated previously by introducing G13997A mtDNA from mouse tumor cells into mouse embryonic stem cells, we provide convincing evidence supporting part of the abovementioned hypothesis by showing that G13997A mtDNA regulates diabetes development, lymphoma formation, and metastasis-but not aging-in this model. reactive oxygen species generating mutation | Warburg effect | chromosome aberration | lactic acidosis | hyperglycemia P athogenic mitochondrial DNA (mtDNA) mutations that induce significant mitochondrial respiration defects are responsible for mitochondrial diseases (1, 2) and could also be involved in aging and age-associated disorders, including tumor development (1-5). On the other hand, mitochondrial respiration defects caused by nuclear DNA mutations and the resultant enhanced glycolysis under normoxic conditions, i.e., the Warburg effect, are proposed to be involved in tumor development (6-9). Because pathogenic mtDNA mutations also induce mitochondrial respiration defects and up-regulation of aerobic glycolysis, accumulation of these mtDNA mutations with age could also be responsible for tumor development. In addition, it is possible that mtDNA mutations regulate tumor development as a consequence of overproduction of reactive oxygen species (ROS) and the resultant induction of genetic instability (1, 2, 10). In fact, somatic mtDNA mutations are preferentially accumulated in human tumor cells (11-13), and a germline mtDNA mutation (A8344G) in the tRNA Lys gene has been found in lipomas (benign adipose tissue tumors) (14). However, there is as yet no direct evidence for the contribution of mtDNA mutations to aging and tumor development, because of the difficulty of excluding the possible contribution of nuclear DNA mutations, including copy-number variants (CNVs), to these processes (2, 15).Our previous study (16) resolved this issue by using complete mtDNA exchange technology between mouse normal and tumor cells, and we showed that exogenously introduced mtDNA does not affect tumorigenicity. In contrast, our recent study (17) performed exchange of mtDNA between poorly and highly metastatic mouse tumor cells, providing convincing evidence that the somatic mtDNA mutation G13997A in the ND6 gene, which encodes one of the subunits of respiration complex I (NADH dehydrogenase), re...

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Section: Resultsmentioning

confidence: 83%

Specific mitochondrial DNA mutation in mice regulates diabetes and lymphoma development

Hashizume

Shimizu

Yokota

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…Thus, respiration-deficient spermatocytes could not complete meiosis, and these cells were removed by apoptosis. Because the ⌬mtDNA load differs in each cell (10,12,18), however, spermatocytes carrying a relatively lower proportion of ⌬mtDNA can complete meiosis and transformation into haploid spermatids. These spermatids could differentiate into sperm, but most sperm showed intermediate COX activity (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…⌬mtDNA is similar to pathogenic mutant mtDNA with the common deletion in human mitochondrial diseases (10). When mito-mice were generated by introduction of mitochondria carrying ⌬mtDNA into zygotes of C57BL͞6J (B6) mice, these mice carrying Ͼ80% mtDNA showed mitochondrial respiration defects and the resultant mitochondrial diseases (9,11,12). The great advantages of mito-mice are that they all share exactly the same nuclear genomic background, and their genetic variation is restricted to the proportions of the introduced pathogenic ⌬mtDNA.…”

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confidence: 99%

Mitochondria-related male infertility

Nakada

Sato

Yoshida

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Approximately 15% of human couples are affected by infertility, and about half of these cases of infertility can be attributed to men, through low sperm motility (asthenozoospermia) or͞and numbers (oligospermia). Because mitochondrial genome (mtDNA) mutations are identified in patients with fertility problems, there is a possibility that mitochondrial respiration defects contribute to male infertility. To address this possibility, we used a transmitochondrial mouse model (mito-mice) carrying wild-type mtDNA and mutant mtDNA with a pathogenic 4,696-bp deletion (⌬mtDNA). Here we show that mitochondrial respiration defects caused by the accumulation of ⌬mtDNA induced oligospermia and asthenozoospermia in the mito-mice. Most sperm from the infertile mito-mice had abnormalities in the middle piece and nucleus. Testes of the infertile mito-mice showed meiotic arrest at the zygotene stage as well as enhanced apoptosis. Thus, our in vivo study using mitomice directly demonstrates that normal mitochondrial respiration is required for mammalian spermatogenesis, and its defects resulting from accumulated mutant mtDNAs cause male infertility. meiosis ͉ mitochondrial diseases ͉ model mice ͉ respiration defects ͉ spermatogenesis

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“…These males with the highest mutant loads also exhibited widespread respiratory deficiencies, and other pathologies associated with mitochondrial disease (myopathy, lactic acidosis, renal failure, deafness). Although male fertility was particularly sensitive to the presence of this mtDNA deletion, the authors noted that females carrying more than 70% of the mutant mtDNA type still produced normal numbers of progeny, at least up until six months of age when they died of mitochondrial pathologies associated with the mutation (Inoue et al 2000, Nakada et al 2004.…”

Section: Mouse Case Studiesmentioning

confidence: 99%

Maternal inheritance of mitochondria: implications for male fertility?

Vaught

Dowling

2018

Reproduction

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Evolutionary theory predicts maternal inheritance of the mitochondria will lead to the accumulation of mutations in the mitochondrial DNA (mtDNA) that impair male fertility, but leave females unaffected. The hypothesis has been referred to as 'Mother's Curse'. There are many examples of mtDNA mutations or haplotypes, in humans and other metazoans, associated with decreases in sperm performance, but seemingly few reports of associations involving female reproductive traits; an observation that has been used to support the Mother's Curse hypothesis. However, it is unclear whether apparent signatures of male bias in mitochondrial genetic effects on fertility reflect an underlying biological bias or a technical bias resulting from a lack of studies to have screened for female effects. Here, we conduct a systematic literature search of studies reporting mitochondrial genetic effects on fertility-related traits in gonochoristic metazoans (animals with two distinct sexes). Studies of female reproductive outcomes were sparse, reflecting a large technical sex bias across the literature. We were only able to make a valid assessment of sex specificity of mitochondrial genetic effects in 30% of cases. However, in most of these cases, the effects were male biased, including examples of male bias associated with mtDNA mutations in humans. These results are therefore consistent with the hypothesis that maternal inheritance has enriched mtDNA sequences with mutations that specifically impair male fertility. However, future research that redresses the technical imbalance in studies conducted per sex will be key to enabling researchers to fully assess the wider implications of the Mother's Curse hypothesis to male reproductive biology.Reproduction (2018) 155 R159-R168

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Accumulation of pathogenic ΔmtDNA induced deafness but not diabetic phenotypes in mito-mice

Cited by 40 publications

References 35 publications

Specific mitochondrial DNA mutation in mice regulates diabetes and lymphoma development

Specific mitochondrial DNA mutation in mice regulates diabetes and lymphoma development

Mitochondria-related male infertility

Maternal inheritance of mitochondria: implications for male fertility?

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