Age-induced accumulation of methylmalonic acid promotes tumour progression

Gomes, Ana P.; Ilter, Didem; Low, Vivien; Endress, Jennifer E.; Fernández-García, Juan; Rosenzweig, Adam; Schild, Tanya; Broekaert, Dorien; Ahmed, Adnan; Planque, Mélanie; Elia, Ilaria; Han, Julie; Kinzig, Charles G; Mullarky, Edouard; Mutvei, Anders P.; Asara, John M.; Cabo, Rafael de; Cantley, Lewis C.; Dephoure, Noah; Fendt, Sarah-Maria; Blenis, John

doi:10.1038/s41586-020-2630-0

Cited by 155 publications

(143 citation statements)

References 57 publications

(47 reference statements)

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“…[ 56 ] Last, we should point out that MMA, which increases upon B 12 deficiency, seems generally upregulated in serum of the elderly and, as was very recently found, might mediate tumor progression via its induction of SOX4 expression. [ 57 ]…”

Section: Vitamin B12 and Carcinogenesismentioning

confidence: 99%

Is There a Carcinogenic Risk Attached to Vitamin B₁₂ Deficient Diets and What Should We Do About It? Reviewing the Facts

Loedin

Speijer

2021

Molecular Nutrition Food Res

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The number of individuals partaking in veganism has increased sharply in the last decade. Therefore, it is critical to look at the implications of vegan diets for public health. Although there are multiple health benefits of a vegan diet, studies have also linked the diet with deficiencies in various micronutrients. This study focuses on vitamin B12, because of its critical role in DNA synthesis and methylation. In light of these connections, a critical review of recent scientific literature is conducted to understand the effects of a B12 deficient diet on the genome and epigenome, and whether it can give rise to cancer. It is observed that a B12 deficiency leads to increased uracil misincorporation, leading to impaired DNA synthesis and genomic instability. The deficiency also leads to global hypomethylation of DNA, a hallmark of early carcinogenesis. The findings of this study highlight the need for increased awareness among vegans to ensure adequate B12 intake through supplementation or consumption of fortified products as a preventative measure. Additionally, the biofortification of staple crops and an improved version of fermented products with increased B12 content can be developed when inadequate intake seems otherwise inevitable.

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Section: Vitamin B12 and Carcinogenesismentioning

confidence: 99%

Is There a Carcinogenic Risk Attached to Vitamin B₁₂ Deficient Diets and What Should We Do About It? Reviewing the Facts

Loedin

Speijer

2021

Molecular Nutrition Food Res

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“…For MMA, its exact role in regulation of immune response or inflammation is not clear. Previous study showed that MMA treatment in A549 cells triggered the induction of SOX4 35 , and interestingly, a recent study found that SOX4 can suppress hepatitis B virus replication via inhibiting hepatocyte nuclear factor 4α 45 . The detailed roles of the identified CC-specific metabolites such as MMA, DHOA and mannitol, require further investigation and the potential therapeutic targets should be further experimentally validated.…”

Section: Discussionmentioning

confidence: 95%

“…Besides, MMA is a dicarboxylic acid that is primarily a by-product of propionate metabolism. Previous study showed that the elevated circulating MMA level caused a significant upregulation of Sex-determining region Y box 4 (SOX4) expression and consequently elicited transcriptional reprogramming 35 , while the role of MMA in regulation of immune response and inflammation is unclear.…”

Section: Resultsmentioning

confidence: 99%

Multi-Omic Profiling of Plasma Identify Biomarkers and Pathogenesis of COVID-19 in Children

Wang

Ning

et al. 2021

Preprint

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Although children usually develop less severe disease responding to COVID-19 than adults, little is known about the pathogenesis of COVID-19 in children. Herein, we conducted the plasma proteomic and metabolomic profiling of a cohort of COVID-19 pediatric patients with mild symptoms. Our data show that numerous proteins and metabolites involved in immune as well as anti-inflammatory processes were up-regulated on a larger scale in children than in adults. By developing a machine learning-based pipeline, we prioritized two sets of biomarker combinations, and identified 5 proteins and 5 metabolites as potential children-specific COVID-19 biomarkers. Further study showed that these identified metabolites not only inhibited the expression of pro-inflammatory factors, but also suppressed coronaviral replication, implying that these factors played key roles in protecting pediatric patients from both viral infection and infection-induced inflammation. Together, our study uncovered a protective mechanism responding to COVID-19 in children, and sheds light on potential therapies.

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“…Notably, the methylmalonyl-CoA mutase required to convert propionyl-CoA to succinyl-CoA is B12-dependent, and odd-chain fatty acids and methylmalonic acid (MMA) accumulate in adipocytes only when cultured in media deficient in cobalamin (e.g., DMEM) [199]. In a recent study, increased MMA levels in circulation correlate with increasing age, and MMA was found to promote an epithelialmesenchymal transition (EMT)-like phenotype and contribute to increased tumorigenesis [201].…”

Section: Branched-chain Amino Acidsmentioning

confidence: 99%

Transporters at the Interface between Cytosolic and Mitochondrial Amino Acid Metabolism

2021

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Mitochondria are central organelles that coordinate a vast array of metabolic and biologic functions important for cellular health. Amino acids are intricately linked to the bioenergetic, biosynthetic, and homeostatic function of the mitochondrion and require specific transporters to facilitate their import, export, and exchange across the inner mitochondrial membrane. Here we review key cellular metabolic outputs of eukaryotic mitochondrial amino acid metabolism and discuss both known and unknown transporters involved. Furthermore, we discuss how utilization of compartmentalized amino acid metabolism functions in disease and physiological contexts. We examine how improved methods to study mitochondrial metabolism, define organelle metabolite composition, and visualize cellular gradients allow for a more comprehensive understanding of how transporters facilitate compartmentalized metabolism.

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Age-induced accumulation of methylmalonic acid promotes tumour progression

Cited by 155 publications

References 57 publications

Is There a Carcinogenic Risk Attached to Vitamin B₁₂ Deficient Diets and What Should We Do About It? Reviewing the Facts

Is There a Carcinogenic Risk Attached to Vitamin B₁₂ Deficient Diets and What Should We Do About It? Reviewing the Facts

Multi-Omic Profiling of Plasma Identify Biomarkers and Pathogenesis of COVID-19 in Children

Transporters at the Interface between Cytosolic and Mitochondrial Amino Acid Metabolism

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Age-induced accumulation of methylmalonic acid promotes tumour progression

Cited by 155 publications

References 57 publications

Is There a Carcinogenic Risk Attached to Vitamin B12 Deficient Diets and What Should We Do About It? Reviewing the Facts

Is There a Carcinogenic Risk Attached to Vitamin B12 Deficient Diets and What Should We Do About It? Reviewing the Facts

Multi-Omic Profiling of Plasma Identify Biomarkers and Pathogenesis of COVID-19 in Children

Transporters at the Interface between Cytosolic and Mitochondrial Amino Acid Metabolism

Contact Info

Product

Resources

About

Is There a Carcinogenic Risk Attached to Vitamin B₁₂ Deficient Diets and What Should We Do About It? Reviewing the Facts

Is There a Carcinogenic Risk Attached to Vitamin B₁₂ Deficient Diets and What Should We Do About It? Reviewing the Facts