Emerging Roles for Riboflavin in Functional Rescue of Mitochondrial β-Oxidation Flavoenzymes

Abstract

Riboflavin, commonly known as vitamin B2, is the precursor of flavin cofactors. It is present in our typical diet, and inside the cells it is metabolized to FMN and FAD. As a result of their rather unique and flexible chemical properties these flavins are among the most important redox cofactors present in a large series of different enzymes. A problem in riboflavin metabolism or a low intake of this vitamin will have consequences on the level of FAD and FMN in the cell, resulting in disorders associated with riboflavin deficiency. In a few number of cases, riboflavin deficiency is associated with impaired oxidative folding, cell damage and impaired heme biosynthesis. More relevant are several studies referring reduced activity of enzymes such as dehydrogenases involved in oxidative reactions, respiratory complexes and enzymes from the fatty acid β-oxidation pathway. The role of this vitamin in mitochondrial metabolism, and in particular in fatty acid oxidation, will be discussed in this review. The basic aspects concerning riboflavin and flavin metabolism and deficiency will be addressed, as well as an overview of the role of the different flavoenzymes and flavin chemistry in fatty acid β-oxidation, merging clinical, cellular and biochemical perspectives. A number of recent studies shedding new light on the cellular processes and biological effects of riboflavin supplementation in metabolic disease will also be overviewed. Overall, a deeper understanding of these emerging roles of riboflavin intake is essential to design better therapies.

Metabolic cycles in a circannual hibernator

“…Only metabolites with ANOVA q Ͻ 0.05 are shown. and all three are involved in redox regulation (20,35). The changing levels of these molecules, particularly their rapid depletion at rewarming, are consistent with their playing a central role in ameliorating the potential damage inflicted by oxidative reperfusion upon arousal.…”

“…One of these was a group of three compounds that accumulated during torpor but rapidly diminished early in the arousal process, while the animals were still at low T b . Biliverdin and bilirubin are heme catabolites, and all three compounds have been implicated in redox regulation (35), riboflavin primarily in the context of fatty acid oxidation (20). It appears likely that they are taken up rapidly by other tissues, including liver which demonstrated a perfectly reciprocal pattern of both flavin and biliverdin levels in the same species (32).…”

Low activity of LSD1 elicits a pro-inflammatory gene expression profile in riboflavin-deficient human T Lymphoma Jurkat cells

“…LSD1 is unique among multiple demethylases in that it belongs to the flavin-containing amine oxidase family and utilizes flavin adenine dinucleotide (FAD) as an essential cofactor for catalytic activities (Forneris et al 2005). FAD, produced by adenylation of the vitamin riboflavin, serves as a coenzyme in a large number of redox reactions and a small number of reactions with no net redox change in mammalian metabolism (Bornemann 2002;Henriques et al 2010;Pinto and Rivlin 2013). LSD1 is enriched in gene promoter regions as part of multiprotein gene repression complex (Foster et al 2010;Wang et al 2009;Whyte et al 2012).…”

A Patient with Complex I Deficiency Caused by a Novel ACAD9 Mutation Not Responding to Riboflavin Treatment

“…The mode of action for riboflavin remains elusive, but it has been suggested to increase mitochondrial FAD concentration, which may support FAD binding. This binding could be necessary for the catalytic activity of ACAD9, however, also its folding or stability may improve (Henriques et al 2010). Riboflavin might also function as an electron acceptor, since fibroblasts from patients with deficiency of NDUFS2, a subunit without FAD or FMN binding sites, responded to riboflavin treatment (Bar-Meir et al 2001).…”