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A mutation in the NADH-dehydrogenase subunit 2 suppresses fibroblast aging.

Schauer M, Kottek T, Schönherr M, Bhattacharya A, Ibrahim SM, Hirose M, Köhling R, Fuellen G, Schmitz U, Kunz M - Oncotarget (2015)

Bottom Line: Furthermore, Nd2-mutant fibroblasts expressed lower senescence markers.In agreement, inhibition of p38MAPK with SB203580 enhanced proliferation and reduced cytokine secretion in fibroblasts.In conclusion, Nd2 is a mitochondrial gene, involved in age-related signaling pathways.

View Article: PubMed Central - PubMed

Affiliation: Department of Dermatology, Venereology and Allergology, University of Leipzig, Leipzig 04103, Germany.

ABSTRACT
Mutations of mitochondrial (mt)DNA cause a variety of human diseases and are implicated in premature aging syndromes. Here we investigated a single nucleotide exchange (leucine to methionine) at position nt4738 in the mitochondrial NADH dehydrogenase subunit 2 (Nd2) gene of the respiratory chain. Primary fibroblasts derived from the conplastic mouse strain C57BL/6J-mtALR/LTJ with mutant enzyme, possessed high enzyme activity and ATP production and low ROS production. Furthermore, Nd2-mutant fibroblasts expressed lower senescence markers. Transcriptome analysis revealed that the members of the p38MAPK pathway were significantly downregulated in Nd2-mutant mice. In agreement, inhibition of p38MAPK with SB203580 enhanced proliferation and reduced cytokine secretion in fibroblasts. In Nd2-mutant mouse skin, the amount of Ki67-positive cells was significantly higher than in control skin. The higher amount of Ki67-positive cells and the thicker epidermis in Nd2-mutant mice strongly supported the in vitro data. In conclusion, Nd2 is a mitochondrial gene, involved in age-related signaling pathways.

No MeSH data available.


Related in: MedlinePlus

Measurement of epidermal thickness and Ki67 staining of the skin of Nd2-mutant miceA. Representative photomicrographs of H&E staining of skin sections from control (n = 4) and Nd2-mutant (n = 4) mice, aged 12 months. B. Quantification of the thickness of the epidermis in skin sections from control (n = 4) and Nd2-mutant (n = 4) mice using BZ II analyzer software. ***p < 0.001. Data expressed as mean ± SEM. C. Representative photomicrographs of Ki67 immunofluorescence staining (green) of skin sections from control (n = 5) and Nd2-mutant mice (n = 5), aged 12 month. DAPI was used for counterstaining of cell nuclei. D. Quantification of Ki67-positive cells in skin sections from control and Nd2-mutant mice using Image J software. ***p < 0.001. Data are expressed as mean ± SEM.
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Figure 6: Measurement of epidermal thickness and Ki67 staining of the skin of Nd2-mutant miceA. Representative photomicrographs of H&E staining of skin sections from control (n = 4) and Nd2-mutant (n = 4) mice, aged 12 months. B. Quantification of the thickness of the epidermis in skin sections from control (n = 4) and Nd2-mutant (n = 4) mice using BZ II analyzer software. ***p < 0.001. Data expressed as mean ± SEM. C. Representative photomicrographs of Ki67 immunofluorescence staining (green) of skin sections from control (n = 5) and Nd2-mutant mice (n = 5), aged 12 month. DAPI was used for counterstaining of cell nuclei. D. Quantification of Ki67-positive cells in skin sections from control and Nd2-mutant mice using Image J software. ***p < 0.001. Data are expressed as mean ± SEM.

Mentions: Next, we wondered whether the reduced cellular senescence effects of Nd2-mutant fibroblasts translate into reduced aging of the skin in vivo. The common in vitro marker SA-β-galactosidase showed contradictory results [21, 22] in vivo. For this reason, other senescence markers were preferred like epidermal thickness and the number of Ki67-positive cells in skin of mutated and control mice. Indeed, 12-month-old Nd2-mutant mice showed a thicker epidermis relative to control mice, whose skin was more atrophic (Figure 6A and 6B). This phenomenon is due to a higher number of epidermal keratinocyte layers consistent with the higher proliferation rate of epidermal keratinoyctes in these mice.


A mutation in the NADH-dehydrogenase subunit 2 suppresses fibroblast aging.

Schauer M, Kottek T, Schönherr M, Bhattacharya A, Ibrahim SM, Hirose M, Köhling R, Fuellen G, Schmitz U, Kunz M - Oncotarget (2015)

Measurement of epidermal thickness and Ki67 staining of the skin of Nd2-mutant miceA. Representative photomicrographs of H&E staining of skin sections from control (n = 4) and Nd2-mutant (n = 4) mice, aged 12 months. B. Quantification of the thickness of the epidermis in skin sections from control (n = 4) and Nd2-mutant (n = 4) mice using BZ II analyzer software. ***p < 0.001. Data expressed as mean ± SEM. C. Representative photomicrographs of Ki67 immunofluorescence staining (green) of skin sections from control (n = 5) and Nd2-mutant mice (n = 5), aged 12 month. DAPI was used for counterstaining of cell nuclei. D. Quantification of Ki67-positive cells in skin sections from control and Nd2-mutant mice using Image J software. ***p < 0.001. Data are expressed as mean ± SEM.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4496166&req=5

Figure 6: Measurement of epidermal thickness and Ki67 staining of the skin of Nd2-mutant miceA. Representative photomicrographs of H&E staining of skin sections from control (n = 4) and Nd2-mutant (n = 4) mice, aged 12 months. B. Quantification of the thickness of the epidermis in skin sections from control (n = 4) and Nd2-mutant (n = 4) mice using BZ II analyzer software. ***p < 0.001. Data expressed as mean ± SEM. C. Representative photomicrographs of Ki67 immunofluorescence staining (green) of skin sections from control (n = 5) and Nd2-mutant mice (n = 5), aged 12 month. DAPI was used for counterstaining of cell nuclei. D. Quantification of Ki67-positive cells in skin sections from control and Nd2-mutant mice using Image J software. ***p < 0.001. Data are expressed as mean ± SEM.
Mentions: Next, we wondered whether the reduced cellular senescence effects of Nd2-mutant fibroblasts translate into reduced aging of the skin in vivo. The common in vitro marker SA-β-galactosidase showed contradictory results [21, 22] in vivo. For this reason, other senescence markers were preferred like epidermal thickness and the number of Ki67-positive cells in skin of mutated and control mice. Indeed, 12-month-old Nd2-mutant mice showed a thicker epidermis relative to control mice, whose skin was more atrophic (Figure 6A and 6B). This phenomenon is due to a higher number of epidermal keratinocyte layers consistent with the higher proliferation rate of epidermal keratinoyctes in these mice.

Bottom Line: Furthermore, Nd2-mutant fibroblasts expressed lower senescence markers.In agreement, inhibition of p38MAPK with SB203580 enhanced proliferation and reduced cytokine secretion in fibroblasts.In conclusion, Nd2 is a mitochondrial gene, involved in age-related signaling pathways.

View Article: PubMed Central - PubMed

Affiliation: Department of Dermatology, Venereology and Allergology, University of Leipzig, Leipzig 04103, Germany.

ABSTRACT
Mutations of mitochondrial (mt)DNA cause a variety of human diseases and are implicated in premature aging syndromes. Here we investigated a single nucleotide exchange (leucine to methionine) at position nt4738 in the mitochondrial NADH dehydrogenase subunit 2 (Nd2) gene of the respiratory chain. Primary fibroblasts derived from the conplastic mouse strain C57BL/6J-mtALR/LTJ with mutant enzyme, possessed high enzyme activity and ATP production and low ROS production. Furthermore, Nd2-mutant fibroblasts expressed lower senescence markers. Transcriptome analysis revealed that the members of the p38MAPK pathway were significantly downregulated in Nd2-mutant mice. In agreement, inhibition of p38MAPK with SB203580 enhanced proliferation and reduced cytokine secretion in fibroblasts. In Nd2-mutant mouse skin, the amount of Ki67-positive cells was significantly higher than in control skin. The higher amount of Ki67-positive cells and the thicker epidermis in Nd2-mutant mice strongly supported the in vitro data. In conclusion, Nd2 is a mitochondrial gene, involved in age-related signaling pathways.

No MeSH data available.


Related in: MedlinePlus