Rapid induction of vitamin B12 deficiency in Caenorhabditis elegans cultured in axenic medium

Lysosomal activity regulates Caenorhabditis elegans mitochondrial dynamics through vitamin B12 metabolism

10.1101/2020.04.20.049502 ◽

2020 ◽

Author(s):

Wei Wei ◽

Gary Ruvkun

Keyword(s):

Caenorhabditis Elegans ◽

Vitamin B12 ◽

Mitochondrial Biogenesis ◽

Mitochondrial Dynamics ◽

Mitochondrial Fission ◽

Vitamin B12 Deficiency ◽

Periodic Pattern ◽

C Elegans ◽

Lysosomal Dysfunction ◽

B12 Deficiency

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.

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Vitamin B12 deficiency in Caenorhabditis elegans results in loss of fertility, extended life cycle, and reduced lifespan

FEBS Open Bio ◽

10.1016/j.fob.2013.01.008 ◽

2013 ◽

Vol 3 (1) ◽

pp. 112-117 ◽

Cited By ~ 35

Author(s):

Tomohiro Bito ◽

Yohei Matsunaga ◽

Yukinori Yabuta ◽

Tsuyoshi Kawano ◽

Fumio Watanabe

Keyword(s):

Life Cycle ◽

Caenorhabditis Elegans ◽

Vitamin B12 ◽

Vitamin B12 Deficiency ◽

B12 Deficiency ◽

Extended Life

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Involvement of Spermidine in the Reduced Lifespan of Caenorhabditis elegans During Vitamin B12 Deficiency

Metabolites ◽

10.3390/metabo9090192 ◽

2019 ◽

Vol 9 (9) ◽

pp. 192

Author(s):

Bito ◽

Okamoto ◽

Otsuka ◽

Yabuta ◽

Arima ◽

...

Keyword(s):

Amino Acids ◽

Amino Acid ◽

Caenorhabditis Elegans ◽

Vitamin B12 ◽

Free Amino ◽

Vitamin B12 Deficiency ◽

Limited Information ◽

Adenosylmethionine Decarboxylase ◽

B12 Deficiency ◽

Amino Acid Levels

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.

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Vitamin B12 deficiency results in severe oxidative stress, leading to memory retention impairment in Caenorhabditis elegans

Redox Biology ◽

10.1016/j.redox.2016.10.013 ◽

2017 ◽

Vol 11 ◽

pp. 21-29 ◽

Cited By ~ 27

Author(s):

Tomohiro Bito ◽

Taihei Misaki ◽

Yukinori Yabuta ◽

Takahiro Ishikawa ◽

Tsuyoshi Kawano ◽

...

Keyword(s):

Oxidative Stress ◽

Caenorhabditis Elegans ◽

Vitamin B12 ◽

Vitamin B12 Deficiency ◽

Memory Retention ◽

B12 Deficiency

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

International Journal of Molecular Sciences ◽

10.3390/ijms222312959 ◽

2021 ◽

Vol 22 (23) ◽

pp. 12959

Author(s):

Kyohei Koseki ◽

Aoi Yamamoto ◽

Keisuke Tanimoto ◽

Naho Okamoto ◽

Fei Teng ◽

...

Keyword(s):

Oxidative Stress ◽

Caenorhabditis Elegans ◽

Vitamin B12 ◽

Mrna Expression ◽

Vitamin B12 Deficiency ◽

Amyloid Β ◽

Underlying Mechanism ◽

Amyloid Β Protein ◽

Collagen Biosynthesis ◽

B12 Deficiency

(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.

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55: The Risk of Vitamin B12 Deficiency is Low after Ileal Orthotopic Bladder Substitution

The Journal of Urology ◽

10.1016/s0022-5347(18)37317-8 ◽

2004 ◽

Vol 171 (4S) ◽

pp. 15-15

Author(s):

Urs E. Studer ◽

Richard Aebischer ◽

Katharina Ochsner ◽

Werner W. Hochreiter

Keyword(s):

Vitamin B12 ◽

Vitamin B12 Deficiency ◽

B12 Deficiency ◽

Bladder Substitution

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Bioavailability of Vitamin B12

International Journal for Vitamin and Nutrition Research ◽

10.1024/0300-9831/a000041 ◽

2010 ◽

Vol 80 (45) ◽

pp. 330-335 ◽

Cited By ~ 28

Author(s):

Lindsay Helen Allen

Keyword(s):

Vitamin B12 ◽

Vitamin B12 Deficiency ◽

The Elderly ◽

Radioactive Isotopes ◽

Animal Source Foods ◽

Dietary Requirements ◽

In Vivo Labeling ◽

B12 Deficiency ◽

Vitamin B12 Malabsorption

Vitamin B12 deficiency is common in people of all ages who consume a low intake of animal-source foods, including populations in developing countries. It is also prevalent among the elderly, even in wealthier countries, due to their malabsorption of B12 from food. Several methods have been applied to diagnose vitamin B12 malabsorption, including Schillings test, which is now used rarely, but these do not quantify percent bioavailability. Most of the information on B12 bioavailability from foods was collected 40 to 50 years ago, using radioactive isotopes of cobalt to label the corrinoid ring. The data are sparse, and the level of radioactivity required for in vivo labeling of animal tissues can be prohibitive. A newer method under development uses a low dose of radioactivity as 14C-labeled B12, with measurement of the isotope excreted in urine and feces by accelerator mass spectrometry. This test has revealed that the unabsorbed vitamin is degraded in the intestine. The percent bioavailability is inversely proportional to the dose consumed due to saturation of the active absorption process, even within the range of usual intake from foods. This has important implications for the assessment and interpretation of bioavailability values, setting dietary requirements, and interpreting relationships between intake and status of the vitamin.

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Increased monocyte to HDL cholesterol ratio in vitamin B12 deficiency: is it related to cardiometabolic risk?

International Journal for Vitamin and Nutrition Research ◽

10.1024/0300-9831/a000668 ◽

2020 ◽

pp. 1-8

Author(s):

Sanem Kayhan ◽

Nazli Gulsoy Kirnap ◽

Mercan Tastemur

Keyword(s):

Risk Factors ◽

Blood Pressure ◽

Uric Acid ◽

Vitamin B12 ◽

Cardiometabolic Risk ◽

Vitamin B12 Deficiency ◽

Left Ventricular ◽

Cardiometabolic Risk Factors ◽

B12 Deficiency ◽

Deficiency Group

Abstract. Vitamin B12 deficiency may have indirect cardiovascular effects in addition to hematological and neuropsychiatric symptoms. It was shown that the monocyte count-to-high density lipoprotein cholesterol (HDL-C) ratio (MHR) is a novel cardiovascular marker. In this study, the aim was to evaluate whether MHR was high in patients with vitamin B12 deficiency and its relationship with cardiometabolic risk factors. The study included 128 patients diagnosed with vitamin B12 deficiency and 93 healthy controls. Patients with vitamin B12 deficiency had significantly higher systolic blood pressure (SBP), diastolic blood pressure (DBP), MHR, C-reactive protein (CRP) and uric acid levels compared with the controls (median 139 vs 115 mmHg, p < 0.001; 80 vs 70 mmHg, p < 0.001; 14.2 vs 9.5, p < 0.001; 10.2 vs 4 mg/dl p < 0.001; 6.68 vs 4.8 mg/dl, p < 0.001 respectively). The prevalence of left ventricular hypertrophy was higher in vitamin B12 deficiency group (43.8%) than the control group (8.6%) (p < 0.001). In vitamin B12 deficiency group, a positive correlation was detected between MHR and SBP, CRP and uric acid (p < 0.001 r:0.34, p < 0.001 r:0.30, p < 0.001 r:0.5, respectively) and a significant negative correlation was detected between MHR and T-CHOL, LDL, HDL and B12 (p < 0.001 r: −0.39, p < 0.001 r: −0.34, p < 0.001 r: −0.57, p < 0.04 r: −0.17, respectively). MHR was high in vitamin B12 deficiency group, and correlated with the cardiometabolic risk factors in this group, which were SBP, CRP, uric acid and HDL. In conclusion, MRH, which can be easily calculated in clinical practice, can be a useful marker to assess cardiovascular risk in patients with vitamin B12 deficiency.

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