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Necrotic enlargement of cone photoreceptor cells and the release of high-mobility group box-1 in retinitis pigmentosa

View Article: PubMed Central - PubMed

ABSTRACT

Retinitis pigmentosa (RP) refers to a group of inherited retinal degenerations resulting form rod and cone photoreceptor cell death. The rod cell death due to deleterious genetic mutations has been shown to occur mainly through apoptosis, whereas the mechanisms and features of the secondary cone cell death have not been fully elucidated. Our previous study showed that the cone cell death in rd10 mice, an animal model of RP, involves necrotic features and is partly mediated by the receptor interacting protein kinase. However, the relevancy of necrotic cone cell death in human RP patients remains unknown. In the present study, we showed that dying cone cells in rd10 mice exhibited cellular enlargement, along with necrotic changes such as cellular swelling and mitochondrial rupture. In human eyes, live imaging of cone cells by adaptive optics scanning laser ophthalmoscopy revealed significantly increased percentages of enlarged cone cells in the RP patients compared with the control subjects. The vitreous of the RP patients contained significantly higher levels of high-mobility group box-1, which is released extracellularly associated with necrotic cell death. These findings suggest that necrotic enlargement of cone cells is involved in the process of cone degeneration, and that necrosis may be a novel target to prevent or delay the loss of cone-mediated central vision in RP.

No MeSH data available.


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Necrotic changes of cone cells in the mouse model of retinitis pigmentosa. (a–f) Representative transmission electron microscopy images of the cone photoreceptor cells in wild-type (WT; a–c, n=4) and rd10 mice (e–f, n=4) at P42. The cone cells in the WT mice contained mitochondria with well-defined lamellar cristae (arrow, a and c) and cytoplasm with medium electron density (a–c). The cone cells in the rd10 mice showed swelling and vacuolation of the cytoplasm and disruption of the mitochondrial cristae (arrow, d). The swollen cone inner segments of rd10 mice (asterisk, e) were associated with plasma membrane rupture (arrowhead, f) and mitochondrial disruption (arrow, f) n, nucleus; arrow, mitochondria; arrowhead, disruption of the plasma membrane; asterisk, the inner segment of cone cells. Scale bar, 2 μm (a–d, f), 5 μm (e).
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fig2: Necrotic changes of cone cells in the mouse model of retinitis pigmentosa. (a–f) Representative transmission electron microscopy images of the cone photoreceptor cells in wild-type (WT; a–c, n=4) and rd10 mice (e–f, n=4) at P42. The cone cells in the WT mice contained mitochondria with well-defined lamellar cristae (arrow, a and c) and cytoplasm with medium electron density (a–c). The cone cells in the rd10 mice showed swelling and vacuolation of the cytoplasm and disruption of the mitochondrial cristae (arrow, d). The swollen cone inner segments of rd10 mice (asterisk, e) were associated with plasma membrane rupture (arrowhead, f) and mitochondrial disruption (arrow, f) n, nucleus; arrow, mitochondria; arrowhead, disruption of the plasma membrane; asterisk, the inner segment of cone cells. Scale bar, 2 μm (a–d, f), 5 μm (e).

Mentions: To further characterize the observed enlargement of cone cells in rd10 mice, we next performed transmission electron microscopy (TEM) analysis. As we observed in another study,9 the cone cells in the p42 rd10 mice showed swelling of the cytoplasm and disruption of the mitochondrial cristae structure (Figure 2d). The inner segments of the cone cells of the rd10 mice were substantially swollen, accompanied by the vacuolation of the cytoplasm, plasma membrane discontinuation, and mitochondrial rupture, which are the characteristics of necrosis (Figures 2e and f). These findings demonstrate that necrotic cellular enlargement occurs during cone degeneration in rd10 mice.


Necrotic enlargement of cone photoreceptor cells and the release of high-mobility group box-1 in retinitis pigmentosa
Necrotic changes of cone cells in the mouse model of retinitis pigmentosa. (a–f) Representative transmission electron microscopy images of the cone photoreceptor cells in wild-type (WT; a–c, n=4) and rd10 mice (e–f, n=4) at P42. The cone cells in the WT mice contained mitochondria with well-defined lamellar cristae (arrow, a and c) and cytoplasm with medium electron density (a–c). The cone cells in the rd10 mice showed swelling and vacuolation of the cytoplasm and disruption of the mitochondrial cristae (arrow, d). The swollen cone inner segments of rd10 mice (asterisk, e) were associated with plasma membrane rupture (arrowhead, f) and mitochondrial disruption (arrow, f) n, nucleus; arrow, mitochondria; arrowhead, disruption of the plasma membrane; asterisk, the inner segment of cone cells. Scale bar, 2 μm (a–d, f), 5 μm (e).
© Copyright Policy - open-access
Related In: Results  -  Collection

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fig2: Necrotic changes of cone cells in the mouse model of retinitis pigmentosa. (a–f) Representative transmission electron microscopy images of the cone photoreceptor cells in wild-type (WT; a–c, n=4) and rd10 mice (e–f, n=4) at P42. The cone cells in the WT mice contained mitochondria with well-defined lamellar cristae (arrow, a and c) and cytoplasm with medium electron density (a–c). The cone cells in the rd10 mice showed swelling and vacuolation of the cytoplasm and disruption of the mitochondrial cristae (arrow, d). The swollen cone inner segments of rd10 mice (asterisk, e) were associated with plasma membrane rupture (arrowhead, f) and mitochondrial disruption (arrow, f) n, nucleus; arrow, mitochondria; arrowhead, disruption of the plasma membrane; asterisk, the inner segment of cone cells. Scale bar, 2 μm (a–d, f), 5 μm (e).
Mentions: To further characterize the observed enlargement of cone cells in rd10 mice, we next performed transmission electron microscopy (TEM) analysis. As we observed in another study,9 the cone cells in the p42 rd10 mice showed swelling of the cytoplasm and disruption of the mitochondrial cristae structure (Figure 2d). The inner segments of the cone cells of the rd10 mice were substantially swollen, accompanied by the vacuolation of the cytoplasm, plasma membrane discontinuation, and mitochondrial rupture, which are the characteristics of necrosis (Figures 2e and f). These findings demonstrate that necrotic cellular enlargement occurs during cone degeneration in rd10 mice.

View Article: PubMed Central - PubMed

ABSTRACT

Retinitis pigmentosa (RP) refers to a group of inherited retinal degenerations resulting form rod and cone photoreceptor cell death. The rod cell death due to deleterious genetic mutations has been shown to occur mainly through apoptosis, whereas the mechanisms and features of the secondary cone cell death have not been fully elucidated. Our previous study showed that the cone cell death in rd10 mice, an animal model of RP, involves necrotic features and is partly mediated by the receptor interacting protein kinase. However, the relevancy of necrotic cone cell death in human RP patients remains unknown. In the present study, we showed that dying cone cells in rd10 mice exhibited cellular enlargement, along with necrotic changes such as cellular swelling and mitochondrial rupture. In human eyes, live imaging of cone cells by adaptive optics scanning laser ophthalmoscopy revealed significantly increased percentages of enlarged cone cells in the RP patients compared with the control subjects. The vitreous of the RP patients contained significantly higher levels of high-mobility group box-1, which is released extracellularly associated with necrotic cell death. These findings suggest that necrotic enlargement of cone cells is involved in the process of cone degeneration, and that necrosis may be a novel target to prevent or delay the loss of cone-mediated central vision in RP.

No MeSH data available.


Related in: MedlinePlus