-
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 -
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 -
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 -
International Journal of Molecular... May 2020As an essential vitamin, the role of riboflavin in human diet and health is increasingly being highlighted. Insufficient dietary intake of riboflavin is often reported... (Review)
Review
As an essential vitamin, the role of riboflavin in human diet and health is increasingly being highlighted. Insufficient dietary intake of riboflavin is often reported in nutritional surveys and population studies, even in non-developing countries with abundant sources of riboflavin-rich dietary products. A latent subclinical riboflavin deficiency can result in a significant clinical phenotype when combined with inborn genetic disturbances or environmental and physiological factors like infections, exercise, diet, aging and pregnancy. Riboflavin, and more importantly its derivatives, flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD), play a crucial role in essential cellular processes including mitochondrial energy metabolism, stress responses, vitamin and cofactor biogenesis, where they function as cofactors to ensure the catalytic activity and folding/stability of flavoenzymes. Numerous inborn errors of flavin metabolism and flavoenzyme function have been described, and supplementation with riboflavin has in many cases been shown to be lifesaving or to mitigate symptoms. This review discusses the environmental, physiological and genetic factors that affect cellular riboflavin status. We describe the crucial role of riboflavin for general human health, and the clear benefits of riboflavin treatment in patients with inborn errors of metabolism.
Topics: Acyl-CoA Dehydrogenases; Aging; Animals; Diet; Electron Transport; Energy Metabolism; Fatty Acids; Female; Flavin Mononucleotide; Flavin-Adenine Dinucleotide; Folic Acid; Genetic Variation; Homocysteine; Humans; Immune System; Metabolism, Inborn Errors; Mitochondria; Mutation; Phenotype; Pregnancy; Protein Folding; Riboflavin; Riboflavin Deficiency
PubMed: 32481712
DOI: 10.3390/ijms21113847 -
Genes Jul 2023Riboflavin transporter 1 (RFVT1) deficiency is an ultrarare metabolic disorder due to autosomal dominant pathogenic variants in . The RFVT1 protein is mainly expressed...
Riboflavin transporter 1 (RFVT1) deficiency is an ultrarare metabolic disorder due to autosomal dominant pathogenic variants in . The RFVT1 protein is mainly expressed in the placenta and intestine. To our knowledge, only five cases of RFVT1 deficiency from three families have been reported so far. While newborns and infants with variants mainly showed a multiple acyl-CoA dehydrogenase deficiency-like presentation, individuals identified in adulthood were usually clinically asymptomatic. We report two patients with novel heterozygous variants. Patient 1 presented at the age of 62 with mild hyperammonemia following gastroenteritis. An acylcarnitine analysis in dried blood spots was abnormal with a multiple acyl-CoA dehydrogenase deficiency-like pattern, and genetic analysis confirmed a heterozygous variant, c.68C > A, p. Ser23Tyr. Patient 2 presented with recurrent seizures and hypsarrhythmia at the age of 7 months. Metabolic investigations yielded unremarkable results. However, whole exome sequencing revealed a heterozygous start loss variant, c.3G > A, p. Met1Ile in These two cases expand the clinical spectrum of riboflavin transporter 1 deficiency and demonstrate that symptomatic presentation in adulthood is possible.
Topics: Female; Humans; Infant; Infant, Newborn; Pregnancy; Heterozygote; Multiple Acyl Coenzyme A Dehydrogenase Deficiency; Receptors, G-Protein-Coupled; Riboflavin; Membrane Transport Proteins
PubMed: 37510312
DOI: 10.3390/genes14071408 -
Journal of Inherited Metabolic Disease Jul 2016Riboflavin (vitamin B2) is absorbed in the small intestine by the human riboflavin transporters RFVT1 and RFVT3. A third riboflavin transporter (RFVT2) is expressed in... (Review)
Review
INTRODUCTION
Riboflavin (vitamin B2) is absorbed in the small intestine by the human riboflavin transporters RFVT1 and RFVT3. A third riboflavin transporter (RFVT2) is expressed in the brain. In 2010 it was demonstrated that mutations in the riboflavin transporter genes SLC52A2 (coding for RFVT2) and SLC52A3 (coding for RFVT3) cause a neurodegenerative disorder formerly known as Brown-Vialetto-Van Laere (BVVL) syndrome, now renamed to riboflavin transporter deficiency. Five years after the diagnosis of the first patient we performed a review of the literature to study the presentation, treatment and outcome of patients with a molecularly confirmed diagnosis of a riboflavin transporter deficiency.
METHOD
A search was performed in Medline, Pubmed using the search terms 'Brown-Vialetto-Van Laere syndrome' and 'riboflavin transporter' and articles were screened for case reports of patients with a molecular diagnosis of a riboflavin transporter deficiency.
RESULTS
Reports on a total of 70 patients with a molecular diagnosis of a RFVT2 or RTVT3 deficiency were retrieved. The riboflavin transporter deficiencies present with weakness, cranial nerve deficits including hearing loss, sensory symptoms including sensory ataxia, feeding difficulties and respiratory difficulties which are caused by a sensorimotor axonal neuropathy and cranial neuropathy. Biochemical abnormalities may be absent and the diagnosis can only be made or rejected by molecular analysis of all genes. Treatment with oral supplementation of riboflavin is lifesaving. Therefore, if a riboflavin transporter deficiency is suspected, treatment must be started immediately without first awaiting the results of molecular diagnostics.
Topics: Bulbar Palsy, Progressive; Diagnosis, Differential; Hearing Loss, Sensorineural; Humans; Membrane Transport Proteins; Molecular Diagnostic Techniques; Mutation; Prognosis; Riboflavin Deficiency
PubMed: 26973221
DOI: 10.1007/s10545-016-9924-2 -
Poultry Science Oct 2021This study aimed to evaluate the effects of dietary riboflavin deficiency (RD) on the lipid metabolism of duck breeders and duck embryos. A total of 40 female 40-wk-old...
This study aimed to evaluate the effects of dietary riboflavin deficiency (RD) on the lipid metabolism of duck breeders and duck embryos. A total of 40 female 40-wk-old white Pekin duck breeders were randomly divided into 2 groups, received either RD diet (1.48 mg riboflavin/kg) or control diet (16.48 mg riboflavin/kg, CON) for 14 wk. Each group consisted of 20 duck breeders (10 replicates per group, 2 birds per replicate), and all experiment birds were single-caged. At the end of the experiment, reproductive performance, hepatic riboflavin, hepatic flavin mononucleotide (FMN), hepatic flavin adenine dinucleotide (FAD), hepatic morphology, hepatic lipid contents, and hepatic protein expression of duck breeders and duck embryos were measured. The results showed that the RD had no effect on egg production and egg fertility but reduced egg hatchability, duck embryo weight, hepatic riboflavin, FMN, and FAD status compared to results obtained in the CON group (all P < 0.05). Livers from RD ducks presented enlarged lipid droplets, excessive accumulation of total lipids, triglycerides, and free fatty acids (all P < 0.05). In addition to excessive lipids accumulation, medium-chain specific acyl-CoA dehydrogenase expression was downregulated (P < 0.05), and short-chain specific acyl-CoA dehydrogenase expression was upregulated in maternal and embryonic livers (P < 0.05). RD did not affect maternal hepatic acyl-CoA dehydrogenase family member 9 (ACAD9) expression, but duck embryonic hepatic ACAD9 expression was reduced in the RD group (P < 0.05). Collectively, dietary RD conditioned lower egg hatchability and inhibited the development of duck embryos. Increased accumulation of lipids, both maternal and embryo, was impaired due to the reduced flavin protein expression, which caused inhibition of hepatic lipids utilization. These findings suggest that abnormal duck embryonic growth and low hatchability caused by RD might be associated with disorders of lipid metabolism in maternal as well as embryos.
Topics: Animals; Chickens; Diet; Ducks; Female; Lipid Metabolism; Riboflavin Deficiency
PubMed: 34438327
DOI: 10.1016/j.psj.2021.101342