Metabolic network rewiring of propionate flux compensates vitamin B12 deficiency in C. elegans

Metabolic network rewiring is the rerouting of metabolism through the use of alternate enzymes to adjust pathway flux and accomplish specific anabolic or catabolic objectives. Here, we report the first characterization of two parallel pathways for the breakdown of the short chain fatty acid propionate in Caenorhabditis elegans. Using genetic interaction mapping, gene co-expression analysis, pathway intermediate quantification and carbon tracing, we uncover a vitamin B12-independent propionate breakdown shunt that is transcriptionally activated on vitamin B12 deficient diets, or under genetic conditions mimicking the human diseases propionic- and methylmalonic acidemia, in which the canonical B12-dependent propionate breakdown pathway is blocked. Our study presents the first example of transcriptional vitamin-directed metabolic network rewiring to promote survival under vitamin deficiency. The ability to reroute propionate breakdown according to B12 availability may provide C. elegans with metabolic plasticity and thus a selective advantage on different diets in the wild.

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Effects of Vitamin B12 Deficiency on Amyloid-β Toxicity in Caenorhabditis elegans

Antioxidants ◽

10.3390/antiox10060962 ◽

2021 ◽

Vol 10 (6) ◽

pp. 962

Author(s):

Arif Andra ◽

Shoko Tanigawa ◽

Tomohiro Bito ◽

Atsushi Ishihara ◽

Fumio Watanabe ◽

...

Keyword(s):

Vitamin B12 ◽

Growth Medium ◽

Vitamin B12 Deficiency ◽

Amyloid Β ◽

Aβ Peptides ◽

C Elegans ◽

Aβ Aggregation ◽

B12 Deficiency ◽

The Relationship ◽

Aβ Production

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.

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Lysosomal activity regulatesCaenorhabditis elegansmitochondrial dynamics through vitamin B12 metabolism

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2008021117 ◽

2020 ◽

Vol 117 (33) ◽

pp. 19970-19981 ◽

Cited By ~ 1

Author(s):

Wei Wei ◽

Gary Ruvkun

Keyword(s):

Vitamin B12 ◽

Mitochondrial Biogenesis ◽

Energy Demand ◽

Mitochondrial Fission ◽

Vitamin B12 Deficiency ◽

Periodic Pattern ◽

C Elegans ◽

Lysosomal Dysfunction ◽

Methionine Restriction ◽

B12 Deficiency

Mitochondrial 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 inCaenorhabditis elegansmuscle, but this pattern is disrupted by mutations in the mitochondrial fission component dynamin DRP-1. 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 theC. elegansdynamin mutant on anEscherichia colistrain with low vitamin B12 also strongly suppressed the mitochondrial fission defect. Of the twoC. elegansenzymes 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 thesams-1S-adenosylmethionine synthase also suppresses thedrp-1fission defect, suggesting that vitamin B12 regulates mitochondrial biogenesis and then affects mitochondrial fission via chromatin pathways.

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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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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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