Riboflavin Deficiency-Implications for General Human Health and Inborn Errors of Metabolism

Abstract

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.

Keywords: MADD; acyl-CoA dehydrogenases; electron transport chain; energy metabolism; fatty acid oxidation; folding; inborn errors of metabolism; mitochondria; riboflavin; riboflavin deficiency.

Figure 1

Riboflavin metabolism and its interaction with environmental factors. Riboflavin is absorbed from the gastrointestinal tract predominantly by riboflavin transporter 3 (RFVT3). Inside the gastrointestinal cells, riboflavin can either be further metabolized to flavin mononucleotide (FMN) by riboflavin kinase (RFK) or to flavin adenine dinucleotide (FAD) by FAD synthase (FADS) or transported to the bloodstream by riboflavin transporter 1 (RFVT1) and riboflavin transporter 2 (RFVT2). Riboflavin is distributed via the bloodstream to its destination cells. In addition to being expressed in the gastrointestinal system, RFVT1 is expressed in the placenta, where it carries riboflavin from maternal bloodstream to fetal bloodstream. RFVT2 is expressed all over the body and highly expressed in the brain, endocrine organs, such as pancreas, but also in the liver and muscle tissue. Inside the destination cells, riboflavin is used directly or transformed into either FMN or FAD, which are used as cofactors for several processes. Several factors can affect human riboflavin status, hereunder, genetics, inflammation and infections, exercise, diet and nutrition, aging and pregnancy.

Figure 2

Disease-related flavoenzymes in mitochondrial energy metabolism. Several flavoenzymes are involved in the mitochondrial energy metabolism including fatty acid oxidation, amino acid metabolism and choline metabolism. Acyl-CoA dehydrogenases are involved in fatty acid oxidation and amino acid metabolism, while dimethylglycine dehydrogenase (DMGDH) and sarcosine dehydrogenase (SARDH) participate in choline metabolism. All these dehydrogenases harbor FAD as a redox cofactor, which is reduced to FADH₂ during the dehydrogenation reactions. The dehydrogenases donate the electrons obtained from their substrates to the electron transfer flavoprotein (ETF), and finally to the electron transport chain (ETC) through the ETF-ubiquinone oxidoreductase (ETF-QO), which reduces coenzyme Q10 (CoQ10). The ethylmalonic encephalopathy protein 1 (ETHE1) is connected to the electron transport chain via the sulfide:quinone oxidoreductase (SQOR) and donates electrons to CoQ10. In the assembly and function of complex I and complex II, FMN and FAD, respectively, have important functions. Additionally, both FMN and FAD are crucial for folding and stability of all these flavoenzymes, that, in some cases, explains the benefits of riboflavin supplementation in patients with genetic variants causing primary or secondary dysfunction of flavoenzymes. Riboflavin can also compensate secondary flavin homeostasis derangements. Abbreviations: ACAD9, acyl-CoA dehydrogenase family member 9; ACAD10, acyl-CoA dehydrogenase family member 10; ACAD11, acyl-CoA dehydrogenase family member 11; CI, complex I; CII, complex II; CIII, complex III; CIV, complex IV; CoQ10, coenzyme Q10; CytC, cytochrome C; DMGDH, dimethylglycine dehydrogenase; ETF, electron transfer flavoprotein; ETF-QO, ETF-ubiquinone oxidoreductase; ETHE1, ethylmalonic encephalopathy protein 1; GCDH, glutaryl-CoA dehydrogenase; IBD, isobutyryl-CoA dehydrogenase; IVD, isovaleryl-CoA dehydrogenase; LCAD, long-chain acyl-CoA dehydrogenase; MCAD, medium-chain acyl-CoA dehydrogenase; SARDH, sarcosine dehydrogenase; SBCAD, short-branched chain acyl-CoA dehydrogenase; SCAD, short-chain acyl-CoA dehydrogenase; SQOR, sulfide:quinone oxidoreductase; VLCAD, very long-chain acyl-CoA dehydrogenase.