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Mitochondrial DNA with a large-scale deletion causes two distinct mitochondrial disease phenotypes in mice.

Katada S, Mito T, Ogasawara E, Hayashi J, Nakada K - G3 (Bethesda) (2013)

Bottom Line: Late-stage embryos carrying ≥50% ΔmtDNA showed abnormal hematopoiesis and iron metabolism in livers that were partly similar to PS (PS-like phenotypes), although they did not express sideroblastic anemia that is a typical symptom of PS.More than half of the neonates with PS-like phenotypes died by 1 month after birth, whereas the rest showed a decrease of ΔmtDNA load in the affected tissues, peripheral blood and liver, and they recovered from PS-like phenotypes.The proportion of ΔmtDNA in various tissues of the surviving mito-miceΔ increased with time, and Kearns-Sayre syndrome-like phenotypes were expressed when the proportion of mtDNA in various tissues reached >70-80%.

View Article: PubMed Central - PubMed

Affiliation: Graduate School of Life and Environmental Sciences, International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, Ibaraki 305-8575, Japan.

ABSTRACT
Studies in patients have suggested that the clinical phenotypes of some mitochondrial diseases might transit from one disease to another (e.g., Pearson syndrome [PS] to Kearns-Sayre syndrome) in single individuals carrying mitochondrial (mt) DNA with a common deletion (ΔmtDNA), but there is no direct experimental evidence for this. To determine whether ΔmtDNA has the pathologic potential to induce multiple mitochondrial disease phenotypes, we used trans-mitochondrial mice with a heteroplasmic state of wild-type mtDNA and ΔmtDNA (mito-miceΔ). Late-stage embryos carrying ≥50% ΔmtDNA showed abnormal hematopoiesis and iron metabolism in livers that were partly similar to PS (PS-like phenotypes), although they did not express sideroblastic anemia that is a typical symptom of PS. More than half of the neonates with PS-like phenotypes died by 1 month after birth, whereas the rest showed a decrease of ΔmtDNA load in the affected tissues, peripheral blood and liver, and they recovered from PS-like phenotypes. The proportion of ΔmtDNA in various tissues of the surviving mito-miceΔ increased with time, and Kearns-Sayre syndrome-like phenotypes were expressed when the proportion of mtDNA in various tissues reached >70-80%. Our model mouse study clearly showed that a single ΔmtDNA was responsible for at least two distinct disease phenotypes at different ages and suggested that the level and dynamics of mtDNA load in affected tissues would be important for the onset and transition of mitochondrial disease phenotypes in mice.

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Relationship between early death and ∆mtDNA load in mito-mice∆. (A) Comparison of ∆mtDNA proportion in tail samples from pups and mothers. Open circles and red crosses indicate pups that were alive and dead, respectively, at 34 days after birth. (B) Comparison between first and second litters in terms of pup survival and ∆mtDNA proportion in the tails of pups. Three female mito-mice∆ carrying 28% (Mouse 28), 52% (Mouse 52), and 61% (Mouse 61) ∆mtDNA in their tails just after birth (day 0) were used in this assay. Open circles and red crosses indicate the proportions of ∆mtDNA in the tails of pups that were alive and dead, respectively, at 34 days after birth. Blue symbols indicate the proportions of ∆mtDNA in mother’s tails. (C) Comparison between the first and second deliveries in terms of survival rates of pups from Mouse 28, Mouse 52, and Mouse 61 at day 34 after birth. Data are presented as mean ± SD. Asterisk indicates significant differences (P < 0.05).
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fig2: Relationship between early death and ∆mtDNA load in mito-mice∆. (A) Comparison of ∆mtDNA proportion in tail samples from pups and mothers. Open circles and red crosses indicate pups that were alive and dead, respectively, at 34 days after birth. (B) Comparison between first and second litters in terms of pup survival and ∆mtDNA proportion in the tails of pups. Three female mito-mice∆ carrying 28% (Mouse 28), 52% (Mouse 52), and 61% (Mouse 61) ∆mtDNA in their tails just after birth (day 0) were used in this assay. Open circles and red crosses indicate the proportions of ∆mtDNA in the tails of pups that were alive and dead, respectively, at 34 days after birth. Blue symbols indicate the proportions of ∆mtDNA in mother’s tails. (C) Comparison between the first and second deliveries in terms of survival rates of pups from Mouse 28, Mouse 52, and Mouse 61 at day 34 after birth. Data are presented as mean ± SD. Asterisk indicates significant differences (P < 0.05).

Mentions: Although the aforementioned results indicated that most mito-mice∆ carrying ≥50% ∆mtDNA died early (≤34 days after birth), a substantial proportion of the progeny of mothers carrying >33% ∆mtDNA died very early (day 1 after birth; Figure 2A). Thus, it was unclear that early death was associated with the proportion of ∆mtDNA either in neonates or mothers. If the latter were the case, then the frequency of early death of pups would be expected to increase with the age of the mother, because ∆mtDNA accumulates in various somatic tissues but disappears in eggs with time (Sato et al. 2007). Therefore, we next examined the frequency of early death in the first and second litters of three female mito-mice∆ carrying 28% (Mouse 28), 52% (Mouse 52), and 61% (Mouse 61) ∆mtDNA, respectively, in their tails just after birth. As expected, the proportion of ∆mtDNA was much greater in the first litter than the second litter (Figure 2B). The rate of early death of pups was greatly and significantly greater in the first litter than in the second delivery (Figure 2, B and C; P < 0.05). The proportion of surviving pups from the second litter (Figure 2C) was comparable with that of pups with wild-type B6 mothers (Figure 1B), despite the ∆mtDNA load of the mothers’ tails increasing with time. Average loads of ∆mtDNA in tail samples were 32.4 ± 21.9% (mean ± SD) and 57.4 ± 16.8% in live and dead mito-mice∆ pups, respectively. On the basis of these results, we concluded that early death of mito-mice∆ was caused by ∆mtDNA load in neonates but not in mothers.


Mitochondrial DNA with a large-scale deletion causes two distinct mitochondrial disease phenotypes in mice.

Katada S, Mito T, Ogasawara E, Hayashi J, Nakada K - G3 (Bethesda) (2013)

Relationship between early death and ∆mtDNA load in mito-mice∆. (A) Comparison of ∆mtDNA proportion in tail samples from pups and mothers. Open circles and red crosses indicate pups that were alive and dead, respectively, at 34 days after birth. (B) Comparison between first and second litters in terms of pup survival and ∆mtDNA proportion in the tails of pups. Three female mito-mice∆ carrying 28% (Mouse 28), 52% (Mouse 52), and 61% (Mouse 61) ∆mtDNA in their tails just after birth (day 0) were used in this assay. Open circles and red crosses indicate the proportions of ∆mtDNA in the tails of pups that were alive and dead, respectively, at 34 days after birth. Blue symbols indicate the proportions of ∆mtDNA in mother’s tails. (C) Comparison between the first and second deliveries in terms of survival rates of pups from Mouse 28, Mouse 52, and Mouse 61 at day 34 after birth. Data are presented as mean ± SD. Asterisk indicates significant differences (P < 0.05).
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC3755915&req=5

fig2: Relationship between early death and ∆mtDNA load in mito-mice∆. (A) Comparison of ∆mtDNA proportion in tail samples from pups and mothers. Open circles and red crosses indicate pups that were alive and dead, respectively, at 34 days after birth. (B) Comparison between first and second litters in terms of pup survival and ∆mtDNA proportion in the tails of pups. Three female mito-mice∆ carrying 28% (Mouse 28), 52% (Mouse 52), and 61% (Mouse 61) ∆mtDNA in their tails just after birth (day 0) were used in this assay. Open circles and red crosses indicate the proportions of ∆mtDNA in the tails of pups that were alive and dead, respectively, at 34 days after birth. Blue symbols indicate the proportions of ∆mtDNA in mother’s tails. (C) Comparison between the first and second deliveries in terms of survival rates of pups from Mouse 28, Mouse 52, and Mouse 61 at day 34 after birth. Data are presented as mean ± SD. Asterisk indicates significant differences (P < 0.05).
Mentions: Although the aforementioned results indicated that most mito-mice∆ carrying ≥50% ∆mtDNA died early (≤34 days after birth), a substantial proportion of the progeny of mothers carrying >33% ∆mtDNA died very early (day 1 after birth; Figure 2A). Thus, it was unclear that early death was associated with the proportion of ∆mtDNA either in neonates or mothers. If the latter were the case, then the frequency of early death of pups would be expected to increase with the age of the mother, because ∆mtDNA accumulates in various somatic tissues but disappears in eggs with time (Sato et al. 2007). Therefore, we next examined the frequency of early death in the first and second litters of three female mito-mice∆ carrying 28% (Mouse 28), 52% (Mouse 52), and 61% (Mouse 61) ∆mtDNA, respectively, in their tails just after birth. As expected, the proportion of ∆mtDNA was much greater in the first litter than the second litter (Figure 2B). The rate of early death of pups was greatly and significantly greater in the first litter than in the second delivery (Figure 2, B and C; P < 0.05). The proportion of surviving pups from the second litter (Figure 2C) was comparable with that of pups with wild-type B6 mothers (Figure 1B), despite the ∆mtDNA load of the mothers’ tails increasing with time. Average loads of ∆mtDNA in tail samples were 32.4 ± 21.9% (mean ± SD) and 57.4 ± 16.8% in live and dead mito-mice∆ pups, respectively. On the basis of these results, we concluded that early death of mito-mice∆ was caused by ∆mtDNA load in neonates but not in mothers.

Bottom Line: Late-stage embryos carrying ≥50% ΔmtDNA showed abnormal hematopoiesis and iron metabolism in livers that were partly similar to PS (PS-like phenotypes), although they did not express sideroblastic anemia that is a typical symptom of PS.More than half of the neonates with PS-like phenotypes died by 1 month after birth, whereas the rest showed a decrease of ΔmtDNA load in the affected tissues, peripheral blood and liver, and they recovered from PS-like phenotypes.The proportion of ΔmtDNA in various tissues of the surviving mito-miceΔ increased with time, and Kearns-Sayre syndrome-like phenotypes were expressed when the proportion of mtDNA in various tissues reached >70-80%.

View Article: PubMed Central - PubMed

Affiliation: Graduate School of Life and Environmental Sciences, International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, Ibaraki 305-8575, Japan.

ABSTRACT
Studies in patients have suggested that the clinical phenotypes of some mitochondrial diseases might transit from one disease to another (e.g., Pearson syndrome [PS] to Kearns-Sayre syndrome) in single individuals carrying mitochondrial (mt) DNA with a common deletion (ΔmtDNA), but there is no direct experimental evidence for this. To determine whether ΔmtDNA has the pathologic potential to induce multiple mitochondrial disease phenotypes, we used trans-mitochondrial mice with a heteroplasmic state of wild-type mtDNA and ΔmtDNA (mito-miceΔ). Late-stage embryos carrying ≥50% ΔmtDNA showed abnormal hematopoiesis and iron metabolism in livers that were partly similar to PS (PS-like phenotypes), although they did not express sideroblastic anemia that is a typical symptom of PS. More than half of the neonates with PS-like phenotypes died by 1 month after birth, whereas the rest showed a decrease of ΔmtDNA load in the affected tissues, peripheral blood and liver, and they recovered from PS-like phenotypes. The proportion of ΔmtDNA in various tissues of the surviving mito-miceΔ increased with time, and Kearns-Sayre syndrome-like phenotypes were expressed when the proportion of mtDNA in various tissues reached >70-80%. Our model mouse study clearly showed that a single ΔmtDNA was responsible for at least two distinct disease phenotypes at different ages and suggested that the level and dynamics of mtDNA load in affected tissues would be important for the onset and transition of mitochondrial disease phenotypes in mice.

Show MeSH
Related in: MedlinePlus