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

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 m...

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Autores principales: Colasuonno, Fiorella, Niceforo, Alessia, Marioli, Chiara, Fracassi, Anna, Stregapede, Fabrizia, Massey, Keith, Tartaglia, Marco, Bertini, Enrico, Compagnucci, Claudia, Moreno, Sandra
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Hindawi 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7443020/
https://www.ncbi.nlm.nih.gov/pubmed/32855765
http://dx.doi.org/10.1155/2020/6821247
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author Colasuonno, Fiorella
Niceforo, Alessia
Marioli, Chiara
Fracassi, Anna
Stregapede, Fabrizia
Massey, Keith
Tartaglia, Marco
Bertini, Enrico
Compagnucci, Claudia
Moreno, Sandra
author_facet Colasuonno, Fiorella
Niceforo, Alessia
Marioli, Chiara
Fracassi, Anna
Stregapede, Fabrizia
Massey, Keith
Tartaglia, Marco
Bertini, Enrico
Compagnucci, Claudia
Moreno, Sandra
author_sort Colasuonno, Fiorella
collection PubMed
description 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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spelling pubmed-74430202020-08-26 Mitochondrial and Peroxisomal Alterations Contribute to Energy Dysmetabolism in Riboflavin Transporter Deficiency Colasuonno, Fiorella Niceforo, Alessia Marioli, Chiara Fracassi, Anna Stregapede, Fabrizia Massey, Keith Tartaglia, Marco Bertini, Enrico Compagnucci, Claudia Moreno, Sandra Oxid Med Cell Longev Research Article 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. Hindawi 2020-08-12 /pmc/articles/PMC7443020/ /pubmed/32855765 http://dx.doi.org/10.1155/2020/6821247 Text en Copyright © 2020 Fiorella Colasuonno et al. http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Colasuonno, Fiorella
Niceforo, Alessia
Marioli, Chiara
Fracassi, Anna
Stregapede, Fabrizia
Massey, Keith
Tartaglia, Marco
Bertini, Enrico
Compagnucci, Claudia
Moreno, Sandra
Mitochondrial and Peroxisomal Alterations Contribute to Energy Dysmetabolism in Riboflavin Transporter Deficiency
title Mitochondrial and Peroxisomal Alterations Contribute to Energy Dysmetabolism in Riboflavin Transporter Deficiency
title_full Mitochondrial and Peroxisomal Alterations Contribute to Energy Dysmetabolism in Riboflavin Transporter Deficiency
title_fullStr Mitochondrial and Peroxisomal Alterations Contribute to Energy Dysmetabolism in Riboflavin Transporter Deficiency
title_full_unstemmed Mitochondrial and Peroxisomal Alterations Contribute to Energy Dysmetabolism in Riboflavin Transporter Deficiency
title_short Mitochondrial and Peroxisomal Alterations Contribute to Energy Dysmetabolism in Riboflavin Transporter Deficiency
title_sort mitochondrial and peroxisomal alterations contribute to energy dysmetabolism in riboflavin transporter deficiency
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7443020/
https://www.ncbi.nlm.nih.gov/pubmed/32855765
http://dx.doi.org/10.1155/2020/6821247
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