Identification of transmembrane protein 237 as a novel interactor with the intestinal riboflavin transporter-3 (RFVT-3): role in functionality and cell biology

Sabui, Subrata; Subramanian, Veedamali S.; Pham, Quang N.; Said, Hamid M.

doi:10.1152/ajpcell.00029.2019

Cited by 9 publications

(5 citation statements)

References 45 publications

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“…When SLC52A2 and SLC52A3 RF transport into the cell is reduced, its limited availability can compromise several vital processes [ 28 , 29 ]. It is therefore likely that mitochondria and peroxisomes are impaired in their integrity and bioenergetics in RTD syndrome.…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial and Peroxisomal Alterations Contribute to Energy Dysmetabolism in Riboflavin Transporter Deficiency

Colasuonno

Niceforo

Marioli

et al. 2020

Oxidative Medicine and Cellular Longevity

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Riboflavin transporter deficiency (RTD) is a childhood-onset neurodegenerative disorder characterized by progressive pontobulbar palsy, sensory and motor neuron degeneration, sensorineural hearing loss, and optic atrophy. As riboflavin (RF) is the precursor of FAD and FMN, we hypothesize that both mitochondrial and peroxisomal energy metabolism pathways involving flavoproteins could be directly affected in RTD, thus impacting cellular redox status. In the present work, we used induced pluripotent stem cells (iPSCs) from RTD patients to investigate morphofunctional features, focusing on mitochondrial and peroxisomal compartments. Using this model, we document the following RTD-associated alterations: (i) abnormal colony-forming ability and loss of cell-cell contacts, revealed by light, electron, and confocal microscopy, using tight junction marker ZO-1; (ii) mitochondrial ultrastructural abnormalities, involving shape, number, and intracellular distribution of the organelles, as assessed by focused ion beam/scanning electron microscopy (FIB/SEM); (iii) redox imbalance, with high levels of superoxide anion, as assessed by MitoSOX assay accompanied by abnormal mitochondrial polarization state, evaluated by JC-1 staining; (iv) altered immunofluorescence expression of antioxidant systems, namely, glutathione, superoxide dismutase 1 and 2, and catalase, as assessed by quantitatively evaluated confocal microscopy; and (v) peroxisomal downregulation, as demonstrated by levels and distribution of fatty acyl β-oxidation enzymes. RF supplementation results in amelioration of cell phenotype and rescue of redox status, which was associated to improved ultrastructural features of mitochondria, thus strongly supporting patient treatment with RF, to restore mitochondrial- and peroxisomal-related aspects of energy dysmetabolism and oxidative stress in RTD syndrome.

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Section: Introductionmentioning

confidence: 99%

Mitochondrial and Peroxisomal Alterations Contribute to Energy Dysmetabolism in Riboflavin Transporter Deficiency

Colasuonno

Niceforo

Marioli

et al. 2020

Oxidative Medicine and Cellular Longevity

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“…Solute carriers (SLC) transport diverse substrates through membranes such as inorganic ions, amino acids, lipids, and drugs [36,37]. Recently, the SLC52 transporter family has been identified, consisting of riboflavin transporters: RFVT1/SLC52A1, RFVT2/SLC52A2, and RFVT3/SLC52A3 [38][39][40][41][42][43]. RFVT1 and RFVT2 show the most similarity to each other (86.7% amino acid identity), while RFVT3 shows only 42.9% identity with RFVT1 and 44.1% with RFVT2 [43].…”

Section: Riboflavin Transportersmentioning

confidence: 99%

Riboflavin-Targeted Drug Delivery

Darguzyte

Drude

Lammers

et al. 2020

Cancers

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Active targeting can improve the retention of drugs and drug delivery systems in tumors, thereby enhancing their therapeutic efficacy. In this context, vitamin receptors that are overexpressed in many cancers are promising targets. In the last decade, attention and research were mainly centered on vitamin B9 (folate) targeting; however, the focus is slowly shifting towards vitamin B2 (riboflavin). Interestingly, while the riboflavin carrier protein was discovered in the 1960s, the three riboflavin transporters (RFVT 1-3) were only identified recently. It has been shown that riboflavin transporters and the riboflavin carrier protein are overexpressed in many tumor types, tumor stem cells, and the tumor neovasculature. Furthermore, a clinical study has demonstrated that tumor cells exhibit increased riboflavin metabolism as compared to normal cells. Moreover, riboflavin and its derivatives have been conjugated to ultrasmall iron oxide nanoparticles, polyethylene glycol polymers, dendrimers, and liposomes. These conjugates have shown a high affinity towards tumors in preclinical studies. This review article summarizes knowledge on RFVT expression in healthy and pathological tissues, discusses riboflavin internalization pathways, and provides an overview of RF-targeted diagnostics and therapeutics.

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“…Besides its important role as an energetic substrate in intestinal epithelial cells, butyrate is involved in the regulation of immune cell by modulating different processes of intestinal epithelial cells and leukocytes through the activation of G protein-coupled receptors and the modulation of the activity of enzymes and transcription factors including the histone deacetylase [ 56 ]. An additional mode of action of NaB could involve the increase of expression of TMEM237, a transmembrane protein encoded by the ALS2CR4 gene, which directly interacts with RFVT3 ensuring its stability [ 57 ].…”

Section: Rf Transportersmentioning

confidence: 99%

“…TNF-α addition to Caco-2 cells reduced the expression of RFVT1 and 3 [ 58 ]. Its effect could be also mediated via a reduction of the level of expression of the TMEM237 protein [ 57 ]. The relevance of NF- k B in regulating RFVT3 expression, upon TNF-α stimulation due to Rf deficiency has been recently proposed also in ESCC [ 43 ].…”

Section: Rf Transportersmentioning

confidence: 99%

Development of Novel Experimental Models to Study Flavoproteome Alterations in Human Neuromuscular Diseases: The Effect of Rf Therapy

Tolomeo

Nisco

Leone

et al. 2020

IJMS

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Inborn errors of Riboflavin (Rf) transport and metabolism have been recently related to severe human neuromuscular disorders, as resulting in profound alteration of human flavoproteome and, therefore, of cellular bioenergetics. This explains why the interest in studying the “flavin world”, a topic which has not been intensively investigated before, has increased much over the last few years. This also prompts basic questions concerning how Rf transporters and FAD (flavin adenine dinucleotide) -forming enzymes work in humans, and how they can create a coordinated network ensuring the maintenance of intracellular flavoproteome. The concept of a coordinated cellular “flavin network”, introduced long ago studying humans suffering for Multiple Acyl-CoA Dehydrogenase Deficiency (MADD), has been, later on, addressed in model organisms and more recently in cell models. In the frame of the underlying relevance of a correct supply of Rf in humans and of a better understanding of the molecular rationale of Rf therapy in patients, this review wants to deal with theories and existing experimental models in the aim to potentiate possible therapeutic interventions in Rf-related neuromuscular diseases.

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Identification of transmembrane protein 237 as a novel interactor with the intestinal riboflavin transporter-3 (RFVT-3): role in functionality and cell biology

Cited by 9 publications

References 45 publications

Mitochondrial and Peroxisomal Alterations Contribute to Energy Dysmetabolism in Riboflavin Transporter Deficiency

Mitochondrial and Peroxisomal Alterations Contribute to Energy Dysmetabolism in Riboflavin Transporter Deficiency

Riboflavin-Targeted Drug Delivery

Development of Novel Experimental Models to Study Flavoproteome Alterations in Human Neuromuscular Diseases: The Effect of Rf Therapy

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