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Colasuonno F, Bertini E, Tartaglia M, et al. Mitochondrial Abnormalities in Induced Pluripotent Stem Cells-Derived Motor Neurons from Patients with Riboflavin Transporter Deficiency. Antioxidants (Basel). 2020;9(12)doi: 10.3390/antiox9121252.
Colasuonno, F., Bertini, E., Tartaglia, M., Compagnucci, C., & Moreno, S. (2020). Mitochondrial Abnormalities in Induced Pluripotent Stem Cells-Derived Motor Neurons from Patients with Riboflavin Transporter Deficiency. Antioxidants (Basel, Switzerland), 9(12), . https://doi.org/10.3390/antiox9121252
Colasuonno, Fiorella, et al. "Mitochondrial Abnormalities in Induced Pluripotent Stem Cells-Derived Motor Neurons from Patients with Riboflavin Transporter Deficiency." Antioxidants (Basel, Switzerland) vol. 9,12 (2020). doi: https://doi.org/10.3390/antiox9121252
Colasuonno F, Bertini E, Tartaglia M, Compagnucci C, Moreno S. Mitochondrial Abnormalities in Induced Pluripotent Stem Cells-Derived Motor Neurons from Patients with Riboflavin Transporter Deficiency. Antioxidants (Basel). 2020 Dec 09;9(12). doi: 10.3390/antiox9121252. PMID: 33317017; PMCID: PMC7763948.
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Antioxidants (Basel). 2020 Dec 09;9(12). doi: 10.3390/antiox9121252.

Mitochondrial Abnormalities in Induced Pluripotent Stem Cells-Derived Motor Neurons from Patients with Riboflavin Transporter Deficiency.

Antioxidants (Basel, Switzerland)

Fiorella Colasuonno, Enrico Bertini, Marco Tartaglia, Claudia Compagnucci, Sandra Moreno

Affiliations

  1. Department of Science, LIME, University of Roma Tre, 00146 Rome, Italy.
  2. Genetics and Rare Diseases Research Division, IRCCS Ospedale Pediatrico Bambino Gesù, 00146 Rome, Italy.
  3. Unit of Neuromuscular and Neurodegenerative Diseases, Laboratory of Molecular Medicine, Department of Neuroscience, IRCCS Ospedale Pediatrico Bambino Gesù, 00146 Rome, Italy.

PMID: 33317017 PMCID: PMC7763948 DOI: 10.3390/antiox9121252

Abstract

Riboflavin transporter deficiency (RTD) is a childhood-onset neurodegenerative disorder characterized by sensorineural deafness and motor neuron degeneration. Since riboflavin plays key functions in biological oxidation-reduction reactions, energy metabolism pathways involving flavoproteins are affected in RTD. We recently generated induced pluripotent stem cell (iPSC) lines from affected individuals as an in vitro model of the disease and documented mitochondrial impairment in these cells, dramatically impacting cell redox status. This work extends our study to motor neurons (MNs), i.e., the cell type most affected in patients with RTD. Altered intracellular distribution of mitochondria was detected by confocal microscopic analysis (following immunofluorescence for superoxide dismutase 2 (SOD2), as a dual mitochondrial and antioxidant marker), and βIII-Tubulin, as a neuronal marker. We demonstrate significantly lower SOD2 levels in RTD MNs, as compared to their healthy counterparts. Mitochondrial ultrastructural abnormalities were also assessed by focused ion beam/scanning electron microscopy. Moreover, we investigated the effects of combination treatment using riboflavin and N-acetylcysteine, which is a widely employed antioxidant. Overall, our findings further support the potential of patient-specific RTD models and provide evidence of mitochondrial alterations in RTD-related iPSC-derived MNs-emphasizing oxidative stress involvement in this rare disease. We also provide new clues for possible therapeutic strategies aimed at correcting mitochondrial defects, based on the use of antioxidants.

Keywords: SOD2; antioxidants; electron microscopy; energy metabolism; mitochondria; motor neurons; neurodegeneration; oxidative stress; riboflavin transporter deficiency

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