Abstract
Riboflavin, known as vitamin B2, a water-soluble vitamin, is an essential nutrient in vertebrates, hence adequate dietary intake is imperative. Riboflavin plays a role in a variety of metabolic pathways, serving primarily as an integral component of its crucial biologically active forms, the flavocoenzymes flavin adenine dinucleotide and flavin mononucleotide. These flavocoenzymes ensure the functionality of numerous flavoproteins including dehydrogenases, oxidases, monooxygenases, and reductases, which play pivotal roles in mitochondrial electron transport chain, β-oxidation of fatty acids, redox homeostasis, citric acid cycle, branched-chain amino acid catabolism, chromatin remodeling, DNA repair, protein folding, and apoptosis. Unsurprisingly, impairment of flavin homeostasis in humans has been linked to various diseases including neuromuscular and neurological disorders, abnormal fetal development, and cardiovascular diseases. This review presents an overview of riboflavin metabolism, its role in mitochondrial function, primary and secondary flavocoenzyme defects associated with mitochondrial dysfunction, and the role of riboflavin supplementation in these conditions.
Highlights
Riboflavin is the precursor of metabolically active flavocoenzymes which are utilized as cofactors for approximately 90 flavoproteins in numerous enzymatic reactions as either flavin adenine dinucleotide (FAD) (84%) or flavin mononucleotide (FMN) (16%)[1]
The most frequent clinical presentation is the milder myopathic Type III form, which manifests with fluctuating proximal and axial myopathy with exercise intolerance and occasionally respiratory insufficiency[138] or rhabdomyolysis, often with hepatomegaly, encephalopathy, and episodic lethargy, as well as vomiting and hypoglycemia often triggered by metabolic stress, episodes of which have been lethal in 5% of patients[140]
AIFM1 mutations have been associated with wide spectrum of clinical phenotypes with X-linked recessive inheritance including a severe, early-onset mitochondrial encephalomyopathy with combined oxidative phosphorylation deficiency[155], prenatal ventriculomegaly[156], the Cowchock syndrome, an X-linked Charcot-Marie-Tooth disease (CMTX4) with axonal sensorimotor neuropathy, deafness and cognitive impairment, [157] auditory neuropathy spectrum disorder, [158] spondyloepimetaphyseal dysplasia with mental retardation[159], and, more recently, cerebellar ataxia partially responsive to riboflavin[160]
Summary
Riboflavin is the precursor of metabolically active flavocoenzymes which are utilized as cofactors for approximately 90 flavoproteins in numerous enzymatic reactions as either flavin adenine dinucleotide (FAD) (84%) or flavin mononucleotide (FMN) (16%)[1]. In contrast to patients with other nuclear encoded Complex I defects who typically have a severe clinical presentation and associated early death, it has been suggested that pathogenic variants in the FOXRED1 gene result in partial loss of function and are probably hypomorphic due to the longer survival of patients[61].
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