Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Mitochondrial Abnormalities in iPSC-Derived Motor Neurons From Patients With Riboflavin Transporter Deficiency

Version 1 : Received: 9 November 2020 / Approved: 12 November 2020 / Online: 12 November 2020 (18:14:17 CET)

How to cite: Colasuonno, F.; Bertini, E.; Tartaglia, M.; Compagnucci, C.; Moreno, S. Mitochondrial Abnormalities in iPSC-Derived Motor Neurons From Patients With Riboflavin Transporter Deficiency. Preprints 2020, 2020110360 (doi: 10.20944/preprints202011.0360.v1). Colasuonno, F.; Bertini, E.; Tartaglia, M.; Compagnucci, C.; Moreno, S. Mitochondrial Abnormalities in iPSC-Derived Motor Neurons From Patients With Riboflavin Transporter Deficiency. Preprints 2020, 2020110360 (doi: 10.20944/preprints202011.0360.v1).

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 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. In the present work, we extend our study to motor neurons (MNs), i.e., the cell type mostly 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 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.

Subject Areas

Riboflavin transporter deficiency; motor neurons; mitochondria; energy metabolism; electron microscopy; antioxidants; SOD2; oxidative stress; neurodegeneration

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