The fine tuning of drp1-dependent mitochondrial remodeling and autophagy controls neuronal differentiation

Chiara Vantaggiato, Marianna Castelli, Matteo Giovarelli, Genny Orso, Maria Teresa Bassi, Emilio Clementi, Clara De Palma

Research output: Contribution to journalArticle

Abstract

Mitochondria play a critical role in neuronal function and neurodegenerative disorders, including Alzheimer’s, Parkinson’s and Huntington diseases and amyotrophic lateral sclerosis, that show mitochondrial dysfunctions associated with excessive fission and increased levels of the fission protein dynamin-related protein 1 (Drp1). Our data demonstrate that Drp1 regulates the transcriptional program induced by retinoic acid (RA), 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 unfolded protein response (UPR) and ER-associated degradation (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 the nuclear transcriptional program.

Original languageEnglish
Article number120
Number of pages20
JournalFrontiers in Cellular Neuroscience
Volume13
DOIs
Publication statusPublished - Jan 29 2019

    Fingerprint

Keywords

  • Autophagy
  • Drp1
  • Mitochondrial fission
  • Mitochondrial remodeling
  • Neuronal differentiation

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

Cite this