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.