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Cell Reports Apr 2021Ablation of Slc22a14 causes male infertility in mice, but the underlying mechanisms remain unknown. Here, we show that SLC22A14 is a riboflavin transporter localized at...
Ablation of Slc22a14 causes male infertility in mice, but the underlying mechanisms remain unknown. Here, we show that SLC22A14 is a riboflavin transporter localized at the inner mitochondrial membrane of the spermatozoa mid-piece and show by genetic, biochemical, multi-omic, and nutritional evidence that riboflavin transport deficiency suppresses the oxidative phosphorylation and reprograms spermatozoa energy metabolism by disrupting flavoenzyme functions. Specifically, we find that fatty acid β-oxidation (FAO) is defective with significantly reduced levels of acyl-carnitines and metabolites from the TCA cycle (the citric acid cycle) but accumulated triglycerides and free fatty acids in Slc22a14 knockout spermatozoa. We demonstrate that Slc22a14-mediated FAO is essential for spermatozoa energy generation and motility. Furthermore, sperm from wild-type mice treated with a riboflavin-deficient diet mimics those in Slc22a14 knockout mice, confirming that an altered riboflavin level causes spermatozoa morphological and bioenergetic defects. Beyond substantially advancing our understanding of spermatozoa energy metabolism, our study provides an attractive target for the development of male contraceptives.
Topics: Animals; Carnitine; Citric Acid Cycle; Diet; Fatty Acids; Female; Fertility; Fertilization in Vitro; Gene Expression; Humans; Infertility, Male; Male; Metabolome; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitochondria; Mitochondrial Membranes; Models, Molecular; Organic Cation Transport Proteins; Oxidative Phosphorylation; Riboflavin; Sperm Motility; Spermatozoa
PubMed: 33882315
DOI: 10.1016/j.celrep.2021.109025 -
Annual Review of Nutrition Aug 2023Riboflavin, in its cofactor forms flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN), plays fundamental roles in energy metabolism, cellular antioxidant... (Review)
Review
Riboflavin, in its cofactor forms flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN), plays fundamental roles in energy metabolism, cellular antioxidant potential, and metabolic interactions with other micronutrients, including iron, vitamin B, and folate. Severe riboflavin deficiency, largely confined to low-income countries, clinically manifests as cheilosis, angular stomatitis, glossitis, seborrheic dermatitis, and severe anemia with erythroid hypoplasia. Subclinical deficiency may be much more widespread, including in high-income countries, but typically goes undetected because riboflavin biomarkers are rarely measured in human studies. There are adverse health consequences of low and deficient riboflavin status throughout the life cycle, including anemia and hypertension, that could contribute substantially to the global burden of disease. This review considers the available evidence on causes, detection, and consequences of riboflavin deficiency, ranging from clinical deficiency signs to manifestations associated with less severe deficiency, and the related research, public health, and policy priorities.
Topics: Humans; Riboflavin Deficiency; Riboflavin; Causality; Antioxidants; Bone Marrow Failure Disorders; Disease Progression; Lip Diseases
PubMed: 37603429
DOI: 10.1146/annurev-nutr-061121-084407 -
Practical Neurology Mar 2024Strachan's syndrome comprises a triad of optic, auditory and painful sensory peripheral neuropathy. It has been recognised since the late 19th century and is presumed to... (Review)
Review
Strachan's syndrome comprises a triad of optic, auditory and painful sensory peripheral neuropathy. It has been recognised since the late 19th century and is presumed to result from nutritional deficiency. Patients present acute or subacutely after a period of systemic illness, weight loss or, most commonly, dietary restriction, especially veganism, which can cause riboflavin (vitamin B) and vitamin B deficiencies. The syndrome is more common in people who are black British and often of Jamaican descent. We describe the clinical phenotype using a typical case example, review other endemic nutritional peripheral neuropathies and discuss the potential benefit of riboflavin as a treatment.
Topics: Humans; Peripheral Nervous System Diseases; Riboflavin Deficiency; Optic Nerve Diseases; Riboflavin; Vitamins; Vitamin B 12 Deficiency
PubMed: 38290841
DOI: 10.1136/pn-2023-003822 -
Clinical Drug Investigation Jun 2021Riboflavin is classified as one of the water-soluble B vitamins. It is part of the functional group of flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD)... (Review)
Review
Riboflavin is classified as one of the water-soluble B vitamins. It is part of the functional group of flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD) cofactors and is required for numerous flavoprotein-catalysed reactions. Riboflavin has important antioxidant properties, essential for correct cell functioning. It is required for the conversion of oxidised glutathione to the reduced form and for the mitochondrial respiratory chain as complexes I and II contain flavoprotein reductases and electron transferring flavoproteins. Riboflavin deficiency has been demonstrated to impair the oxidative state of the body, especially in relation to lipid peroxidation status, in both animal and human studies. In the nervous system, riboflavin is essential for the synthesis of myelin and its deficiency can determine the disruption of myelin lamellae. The inherited condition of restricted riboflavin absorption and utilisation, reported in about 10-15% of world population, warrants further investigation in relation to its association with the main neurodegenerative diseases. Several successful trials testing riboflavin for migraine prevention were performed, and this drug is currently classified as a Level B medication for migraine according to the American Academy of Neurology evidence-based rating, with evidence supporting its efficacy. Brown-Vialetto-Van Laere syndrome and Fazio-Londe diseases are now renamed as "riboflavin transporter deficiency" because these are autosomal recessive diseases caused by mutations of SLC52A2 and SLC52A3 genes that encode riboflavin transporters. High doses of riboflavin represent the mainstay of the therapy of these diseases and high doses of riboflavin should be rapidly started as soon as the diagnosis is suspected and continued lifelong. Remarkably, some mitochondrial diseases respond to supplementation with riboflavin. These include multiple acyl-CoA-dehydrogenase deficiency (which is caused by ETFDH gene mutations in the majority of the cases, or mutations in the ETFA and ETFB genes in a minority), mutations of ACAD9 gene, mutations of AIFM1 gene, mutations of the NDUFV1 and NDUFV2 genes. Therapeutic riboflavin administration has been tried in other neurological diseases, including stroke, multiple sclerosis, Friedreich's ataxia and Parkinson's disease. Unfortunately, the design of these clinical trials was not uniform, not allowing to accurately assess the real effects of this molecule on the disease course. In this review we analyse the properties of riboflavin and its possible effects on the pathogenesis of different neurological diseases, and we will review the current indications of this vitamin as a therapeutic intervention in neurology.
Topics: Animals; Bulbar Palsy, Progressive; Electron-Transferring Flavoproteins; Hearing Loss, Sensorineural; Humans; Membrane Transport Proteins; Multiple Acyl Coenzyme A Dehydrogenase Deficiency; Mutation; Nervous System Diseases; Riboflavin
PubMed: 33886098
DOI: 10.1007/s40261-021-01038-1 -
Roczniki Panstwowego Zakladu Higieny 2021DNA methylation is a reversible epigenetic modification that plays a crucial role in transcriptional gene silencing. Both excessive (hypermethylation) and reduced DNA...
DNA methylation is a reversible epigenetic modification that plays a crucial role in transcriptional gene silencing. Both excessive (hypermethylation) and reduced DNA methylation (hypomethylation) can contribute to the disturbance of the proper course of many important processes in the human body. The aim of the study was to discuss the relationship between methyl nutrients and the DNA methylation process in the course of selected diseases in adults. Methyl nutrients include folates (vitamin B9), riboflavin (vitamin B2), cobalamin (vitamin B12), pyridoxine (vitamin B6) and choline (vitamin B4), as well as methionine and betaine. These substances play the role of both substrates and cofactors in transformations related to one-carbon metabolism. The deficiency of methyl nutrients in the body can lead to disturbances in SAM synthesis, which is the primary donor of methyl groups in the DNA methylation process. However, the mechanism explaining the discussed relationship has not been fully explained so far. Both the concentration in the body and the intake of folate and vitamin B12 in the diet can, to some extent, have an effect on the level of DNA methylation in healthy people. In comparison, data on the effect of excessive intake of vitamin B12 in the diet on the risk of cancer development are inconsistent. An adequate betaine and choline intake in the diet might not only affect the overall improvement of the DNA methylation profile, but, to some extent, also reduce the risk of cancer, the effect of which can depend on the content of folic acid in the body. Research results on the effect of supplementation of methyl nutrients on the DNA methylation process are inconclusive. It is therefore necessary to conduct further research in this area to draw clear conclusions.
Topics: Adult; Carbon; DNA Methylation; Diet; Epigenesis, Genetic; Folic Acid; Humans; Nutrients; One-Carbon Group Transferases; Vitamin B 12; Vitamin B 6
PubMed: 34114759
DOI: 10.32394/rpzh.2021.0157 -
The American Journal of Clinical... Dec 2022
Topics: Adult; Humans; Riboflavin Deficiency; Vitamin B 6; Riboflavin; Pyridoxine; Genotype; Vitamins; Methylenetetrahydrofolate Reductase (NADPH2)
PubMed: 36264295
DOI: 10.1093/ajcn/nqac269 -
Nutrition Reviews Dec 2022Riboflavin in its coenzyme forms, flavin mononucleotide and flavin adenine dinucleotide, is essential for multiple redox reactions necessary for energy production,... (Review)
Review
Riboflavin in its coenzyme forms, flavin mononucleotide and flavin adenine dinucleotide, is essential for multiple redox reactions necessary for energy production, antioxidant protection, and metabolism of other B vitamins, such as niacin, pyridoxine, and folate. Erythrocyte glutathione reductase activity coefficient (EGRac) is a biomarker of riboflavin status; ratios ≥1.40 are commonly interpreted as indicating biochemical deficiency. Most research on riboflavin status comes from low-income countries and rural settings, which reported high rates of riboflavin deficiency and inadequate intake. However, some studies suggest that riboflavin deficiency, based on the functional indicator EGRac, is also of concern in middle- and high-income countries. Biochemical riboflavin deficiency that does not cause clinical symptoms may contribute to anemia, particularly among women and children. Riboflavin enhances iron absorption, and riboflavin deficiency decreases iron mobilization from stores. The current knowledge on riboflavin's role in metabolic processes and its biochemical status is summarized in this review, and the available evidence on the role of riboflavin in anemia among different populations is discussed.
Topics: Child; Female; Humans; Riboflavin Deficiency; Anemia; Iron
PubMed: 36018769
DOI: 10.1093/nutrit/nuac043