Limits...
Endoplasmic reticulum thiol oxidase deficiency leads to ascorbic acid depletion and noncanonical scurvy in mice.

Zito E, Hansen HG, Yeo GS, Fujii J, Ron D - Mol. Cell (2012)

Bottom Line: These severe abnormalities were associated with an unexpectedly modest delay in disulfide bond formation in secreted proteins but a profound, 5-fold lower procollagen 4-hydroxyproline content and enhanced cysteinyl sulfenic acid modification of ER proteins.In vitro, the presence of a sulfenic acid donor accelerated the oxidative inactivation of ascorbate by an H(2)O(2)-generating system.Compromised ER disulfide relay thus exposes protein thiols to competing oxidation to sulfenic acid, resulting in depletion of ascorbic acid, impaired procollagen proline 4-hydroxylation, and a noncanonical form of scurvy.

View Article: PubMed Central - PubMed

Affiliation: University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Cambridge, UK. ez235@medschl.cam.ac.uk

Show MeSH

Related in: MedlinePlus

Abnormal Connective Tissue in the DM and TM Mice(A) Photomicrographs of the tails and ears of 8-week-old control (Ctrl, as defined in Table 1), DM, and TM littermates. Note the thin and misshapen tail and degenerated pinna of the TM and the abnormally thin but normally proportioned tail and smaller pinna of the DM mice.(B) Hematoxylin and eosin (H&E)-stained, Masson’s Trichrome-stained paraffin embedded sections and electron micrographs (EM) of skin from tail of mice of the indicated genotype. Note the abnormally sparse connective tissue fibers in the dermis of the mutant samples (yellow arrowheads in the H&E- and Masson’s Trichrome-stained sections, more conspicuous in the TM than the DM sample) and the dilated ER (arrow) in tissue fibroblasts and abnormal connective tissue fibers (arrowhead) in the mutant EM samples.(C) Collagen mass (measured as 4-hydroxyproline content in an acid hydrolysate of skin, normalized to a standard mass of purified rat tail collagen) per tissue mass recovered from mice of the indicated genotypes. Shown are values obtained in individual samples and the mean of each group (n = 4, ∗∗p < 0.01).
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3473360&req=5

fig2: Abnormal Connective Tissue in the DM and TM Mice(A) Photomicrographs of the tails and ears of 8-week-old control (Ctrl, as defined in Table 1), DM, and TM littermates. Note the thin and misshapen tail and degenerated pinna of the TM and the abnormally thin but normally proportioned tail and smaller pinna of the DM mice.(B) Hematoxylin and eosin (H&E)-stained, Masson’s Trichrome-stained paraffin embedded sections and electron micrographs (EM) of skin from tail of mice of the indicated genotype. Note the abnormally sparse connective tissue fibers in the dermis of the mutant samples (yellow arrowheads in the H&E- and Masson’s Trichrome-stained sections, more conspicuous in the TM than the DM sample) and the dilated ER (arrow) in tissue fibroblasts and abnormal connective tissue fibers (arrowhead) in the mutant EM samples.(C) Collagen mass (measured as 4-hydroxyproline content in an acid hydrolysate of skin, normalized to a standard mass of purified rat tail collagen) per tissue mass recovered from mice of the indicated genotypes. Shown are values obtained in individual samples and the mean of each group (n = 4, ∗∗p < 0.01).

Mentions: TM animals had a conspicuous phenotype: they were less than 70% in weight of their littermates, failed to thrive, and their tails and ears were disproportionately small and misshapen and, in rare survivors, degenerated with time (Figure 2A). Closer scrutiny revealed that DM animals, too, had thin tails and smaller ears, an invariable phenotype that was previously overlooked (Chin et al., 2011).


Endoplasmic reticulum thiol oxidase deficiency leads to ascorbic acid depletion and noncanonical scurvy in mice.

Zito E, Hansen HG, Yeo GS, Fujii J, Ron D - Mol. Cell (2012)

Abnormal Connective Tissue in the DM and TM Mice(A) Photomicrographs of the tails and ears of 8-week-old control (Ctrl, as defined in Table 1), DM, and TM littermates. Note the thin and misshapen tail and degenerated pinna of the TM and the abnormally thin but normally proportioned tail and smaller pinna of the DM mice.(B) Hematoxylin and eosin (H&E)-stained, Masson’s Trichrome-stained paraffin embedded sections and electron micrographs (EM) of skin from tail of mice of the indicated genotype. Note the abnormally sparse connective tissue fibers in the dermis of the mutant samples (yellow arrowheads in the H&E- and Masson’s Trichrome-stained sections, more conspicuous in the TM than the DM sample) and the dilated ER (arrow) in tissue fibroblasts and abnormal connective tissue fibers (arrowhead) in the mutant EM samples.(C) Collagen mass (measured as 4-hydroxyproline content in an acid hydrolysate of skin, normalized to a standard mass of purified rat tail collagen) per tissue mass recovered from mice of the indicated genotypes. Shown are values obtained in individual samples and the mean of each group (n = 4, ∗∗p < 0.01).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3473360&req=5

fig2: Abnormal Connective Tissue in the DM and TM Mice(A) Photomicrographs of the tails and ears of 8-week-old control (Ctrl, as defined in Table 1), DM, and TM littermates. Note the thin and misshapen tail and degenerated pinna of the TM and the abnormally thin but normally proportioned tail and smaller pinna of the DM mice.(B) Hematoxylin and eosin (H&E)-stained, Masson’s Trichrome-stained paraffin embedded sections and electron micrographs (EM) of skin from tail of mice of the indicated genotype. Note the abnormally sparse connective tissue fibers in the dermis of the mutant samples (yellow arrowheads in the H&E- and Masson’s Trichrome-stained sections, more conspicuous in the TM than the DM sample) and the dilated ER (arrow) in tissue fibroblasts and abnormal connective tissue fibers (arrowhead) in the mutant EM samples.(C) Collagen mass (measured as 4-hydroxyproline content in an acid hydrolysate of skin, normalized to a standard mass of purified rat tail collagen) per tissue mass recovered from mice of the indicated genotypes. Shown are values obtained in individual samples and the mean of each group (n = 4, ∗∗p < 0.01).
Mentions: TM animals had a conspicuous phenotype: they were less than 70% in weight of their littermates, failed to thrive, and their tails and ears were disproportionately small and misshapen and, in rare survivors, degenerated with time (Figure 2A). Closer scrutiny revealed that DM animals, too, had thin tails and smaller ears, an invariable phenotype that was previously overlooked (Chin et al., 2011).

Bottom Line: These severe abnormalities were associated with an unexpectedly modest delay in disulfide bond formation in secreted proteins but a profound, 5-fold lower procollagen 4-hydroxyproline content and enhanced cysteinyl sulfenic acid modification of ER proteins.In vitro, the presence of a sulfenic acid donor accelerated the oxidative inactivation of ascorbate by an H(2)O(2)-generating system.Compromised ER disulfide relay thus exposes protein thiols to competing oxidation to sulfenic acid, resulting in depletion of ascorbic acid, impaired procollagen proline 4-hydroxylation, and a noncanonical form of scurvy.

View Article: PubMed Central - PubMed

Affiliation: University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Cambridge, UK. ez235@medschl.cam.ac.uk

Show MeSH
Related in: MedlinePlus