scholarly journals Dityrosine Crosslinking of Collagen and Amyloid-β Peptides Is Formed by Vitamin B12 Deficiency-Generated Oxidative Stress in Caenorhabditis elegans

2021 ◽  
Vol 22 (23) ◽  
pp. 12959
Author(s):  
Kyohei Koseki ◽  
Aoi Yamamoto ◽  
Keisuke Tanimoto ◽  
Naho Okamoto ◽  
Fei Teng ◽  
...  

(1) Background: Vitamin B12 deficiency in Caenorhabditis elegans results in severe oxidative stress and induces morphological abnormality in mutants due to disordered cuticle collagen biosynthesis. We clarified the underlying mechanism leading to such mutant worms due to vitamin B12 deficiency. (2) Results: The deficient worms exhibited decreased collagen levels of up to approximately 59% compared with the control. Although vitamin B12 deficiency did not affect the mRNA expression of prolyl 4-hydroxylase, which catalyzes the formation of 4-hydroxyproline involved in intercellular collagen biosynthesis, the level of ascorbic acid, a prolyl 4-hydroxylase coenzyme, was markedly decreased. Dityrosine crosslinking is involved in the extracellular maturation of worm collagen. The dityrosine level of collagen significantly increased in the deficient worms compared with the control. However, vitamin B12 deficiency hardly affected the mRNA expression levels of bli-3 and mlt-7, which are encoding crosslinking-related enzymes, suggesting that deficiency-induced oxidative stress leads to dityrosine crosslinking. Moreover, using GMC101 mutant worms that express the full-length human amyloid β, we found that vitamin B12 deficiency did not affect the gene and protein expressions of amyloid β but increased the formation of dityrosine crosslinking in the amyloid β protein. (3) Conclusions: Vitamin B12-deficient wild-type worms showed motility dysfunction due to decreased collagen levels and the formation of highly tyrosine-crosslinked collagen, potentially reducing their flexibility. In GMC101 mutant worms, vitamin B12 deficiency-induced oxidative stress triggers dityrosine-crosslinked amyloid β formation, which might promote its stabilization and toxic oligomerization.

Redox Biology ◽  
2017 ◽  
Vol 11 ◽  
pp. 21-29 ◽  
Author(s):  
Tomohiro Bito ◽  
Taihei Misaki ◽  
Yukinori Yabuta ◽  
Takahiro Ishikawa ◽  
Tsuyoshi Kawano ◽  
...  

2017 ◽  
Vol 26 (4) ◽  
pp. 621-625 ◽  
Author(s):  
Tünay Kontaş Aşkar ◽  
olga Büyükleblebici ◽  
Adnan Hismioğulları ◽  
Zeynep Hünkerler

Nutrition ◽  
2012 ◽  
Vol 28 (7-8) ◽  
pp. e23-e26 ◽  
Author(s):  
Masoud Y. Al-Maskari ◽  
Mostafa I. Waly ◽  
Amanat Ali ◽  
Yusra S. Al-Shuaibi ◽  
Allal Ouhtit

Antioxidants ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 962
Author(s):  
Arif Andra ◽  
Shoko Tanigawa ◽  
Tomohiro Bito ◽  
Atsushi Ishihara ◽  
Fumio Watanabe ◽  
...  

High homocysteine (Hcy) levels, mainly caused by vitamin B12 deficiency, have been reported to induce amyloid-β (Aβ) formation and tau hyperphosphorylation in mouse models of Alzheimer’s disease. However, the relationship between B12 deficiency and Aβ aggregation is poorly understood, as is the associated mechanism. In the current study, we used the transgenic C. elegans strain GMC101, which expresses human Aβ1–42 peptides in muscle cells, to investigate the effects of B12 deficiency on Aβ aggregation–associated paralysis. C. elegans GMC101 was grown on nematode growth medium with or without B12 supplementation or with 2-O-α-D-glucopyranosyl-L-ascorbic acid (AsA-2G) supplementation. The worms were age-synchronized by hypochlorite bleaching and incubated at 20 °C. After the worms reached the young adult stage, the temperature was increased to 25 °C to induce Aβ production. Worms lacking B12 supplementation exhibited paralysis faster and more severely than those that received it. Furthermore, supplementing B12-deficient growth medium with AsA-2G rescued the paralysis phenotype. However, AsA-2G had no effect on the aggregation of Aβ peptides. Our results indicated that B12 supplementation lowered Hcy levels and alleviated Aβ toxicity, suggesting that oxidative stress caused by elevated Hcy levels is an important factor in Aβ toxicity.


2018 ◽  
Vol 13 ◽  
pp. 20-25
Author(s):  
Surafel M. Tegegne ◽  
Markandeya Jois ◽  
Matthew R. Flavel ◽  
Damien L. Callahan ◽  
Devin Benheim

2020 ◽  
Author(s):  
Wei Wei ◽  
Gary Ruvkun

ABSTRACTMitochondrial fission and fusion are highly regulated by energy demand and physiological conditions to control the production, activity, and movement of these organelles. Mitochondria are arrayed in a periodic pattern in Caenorhabditis elegans muscle, but this pattern is disrupted by mutations in the mitochondrial fission component dynamin. Here we show that the dramatically disorganized mitochondria caused by a mitochondrial fission-defective dynamin mutation is strongly suppressed to a more periodic pattern by a second mutation in lysosomal biogenesis or acidification. Vitamin B12 is normally imported from the bacterial diet via lysosomal degradation of B12-binding proteins and transport of vitamin B12 to the mitochondrion and cytoplasm. We show that the lysosomal dysfunction induced by gene inactivations of lysosomal biogenesis or acidification factors causes vitamin B12 deficiency. Growth of the C. elegans dynamin mutant on an E. coli strain with low vitamin B12 also strongly suppressed the mitochondrial fission defect. Of the two C. elegans enzymes that require B12, gene inactivation of methionine synthase suppressed the mitochondrial fission defect of a dynamin mutation. We show that lysosomal dysfunction induced mitochondrial biogenesis which is mediated by vitamin B12 deficiency and methionine restriction. S-adenosylmethionine, the methyl donor of many methylation reactions, including histones, is synthesized from methionine by S-adenosylmethionine synthase; inactivation of the sams-1 S-adenosylmethionine synthase also suppresses the drp-1 fission defect, suggesting that vitamin B12 regulates mitochondrial biogenesis and then affects mitochondrial fission via chromatin pathways.SIGNIFICANCE STATEMENTThe balance of mitochondrial fission and fusion, two aspects of mitochondrial dynamics, is important for mitochondrial function. Here we show that Caenorhabditis elegans lysosomal activity regulates mitochondrial dynamics by affecting mitochondrial fission through interfering the metabolism of a micronutrient, vitamin B12. Vitamin B12 is exclusively obtained from diets in animals including C. elegans and humans, and its uptake is mediated by the lysosome. We show that lysosomal dysfunction causes vitamin B12 deficiency that leads to reduction of methionine and S-adenosylmethionine to in turn increase mitochondrial biogenesis and fission. Our study provides an insight on the interactions between mitochondrial function and micronutrient metabolism.


FEBS Open Bio ◽  
2013 ◽  
Vol 3 (1) ◽  
pp. 112-117 ◽  
Author(s):  
Tomohiro Bito ◽  
Yohei Matsunaga ◽  
Yukinori Yabuta ◽  
Tsuyoshi Kawano ◽  
Fumio Watanabe

Metabolites ◽  
2019 ◽  
Vol 9 (9) ◽  
pp. 192
Author(s):  
Bito ◽  
Okamoto ◽  
Otsuka ◽  
Yabuta ◽  
Arima ◽  
...  

Vitamin B12 deficiency leads to various symptoms such as neuropathy, growth retardation, and infertility. Vitamin B12 functions as a coenzyme for two enzymes involved in amino acid metabolisms. However, there is limited information available on whether amino acid disorders caused by vitamin B12 deficiency induce such symptoms. First, free amino acid levels were determined in vitamin B12-deficient Caenorhabditis elegans to clarify the mechanisms underlying the symptoms caused by vitamin B12 deficiency. Various amino acids (valine, leucine, isoleucine, methionine, and cystathionine, among others) metabolized by vitamin B12-dependent enzymes were found to be significantly changed during conditions of B12 deficiency, which indirectly affected certain amino acids metabolized by vitamin B12-independent enzymes. For example, ornithine was significantly increased during vitamin B12 deficiency, which also significantly increased arginase activity. The accumulation of ornithine during vitamin B12 deficiency constitutes the first report. In addition, the biosynthesis of spermidine from ornithine was significantly decreased during vitamin B12 deficiency, likely due to the reduction of S-adenosylmethionine as a substrate for S-adenosylmethionine decarboxylase, which catalyzes the formation of spermidine. Moreover, vitamin B12 deficiency also demonstrated a significant reduction in worm lifespan, which was partially recovered by the addition of spermidine. Collectively, our findings suggest that decreased spermidine is one factor responsible for reduced lifespan in vitamin B12-deficient worms.


Sign in / Sign up

Export Citation Format

Share Document