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Front. Cell. Neurosci. | doi: 10.3389/fncel.2019.00120

The fine tuning of Drp1-dependent mitochondrial remodeling and autophagy controls neuronal differentiation

  • 1Laboratorio di Biologia Molecolare, Istituto Scientifico IRCCS 'E. Medea”, Italy
  • 2Department of Biomedical Sciences and Clinics Luigi Sacco, Faculty of Medicine and Surgery, University of Milan, Italy
  • 3Department of Pharmaceutical and Pharmacological Sciences, School of Medicine and Surgery, University of Padova, Italy
  • 4Unità di Clinica Carmacologica, ASST Fatebenefratelli Sacco, Italy

Mitochondria play a critical role in neuronal function and neurodegenerative disorders, including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis and Huntington, that show mitochondrial dysfunctions associated with excessive fission and increased levels of the fission protein Drp1. Our data demonstrate that Drp1 regulates the transcriptional program induced by retinoic acid, leading to neuronal differentiation. When Drp1 was overexpressed, mitochondria underwent remodeling, but failed to elongate and this enhanced autophagy and apoptosis. When Drp1 was blocked during differentiation by overexpressing the dominant negative form or was silenced, mitochondria maintained the same elongated shape, without remodeling, and this increased cell death. The enhanced apoptosis, observed with both fragmented or elongated mitochondria, was associated with increased induction of UPR and ERAD processes that finally affect neuronal differentiation. These findings suggest that physiological fission and mitochondrial remodeling, associated with early autophagy induction are essential for neuronal differentiation. We thus reveal the importance of mitochondrial changes to generate viable neurons and highlight that, rather than multiple parallel events, mitochondrial changes, autophagy and apoptosis proceed in a stepwise fashion during neuronal differentiation affecting nuclear transcriptional program.

Keywords: DRP1, neuronal differentiation, Mitochondrial remodeling, Autophagy, mitochondrial fission

Received: 14 Sep 2018; Accepted: 11 Mar 2019.

Edited by:

Xin Qi, School of Medicine, Case Western Reserve University, United States

Reviewed by:

Amit U. Joshi, Stanford University, United States
Ozgun Gokce, Ludwig Maximilian University of Munich, Germany  

Copyright: © 2019 Vantaggiato, Castelli, Giovarelli, Orso, Bassi, Clementi and De Palma. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Chiara Vantaggiato, Laboratorio di Biologia Molecolare, Istituto Scientifico IRCCS 'E. Medea”, Bosisio Parini - Lecco, Italy, chiara.vantaggiato@lanostrafamiglia.it