The Fine Tuning of Drp1-Dependent Mitochondrial Remodeling and Autophagy Controls Neuronal Differentiation.

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

doi:10.3389/fncel.2019.00120

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.

Highlights

Mitochondrial dynamics and the balance between fusion and fission are key adaptative mechanisms to the metabolic needs of the cell (Gomes et al, 2011; Schrepfer and Scorrano, 2016)
We found that dynamin-related protein 1 (Drp1) expression levels gradually increased in neural stem cells during retinoic acid (RA) treatment to rich 2.5–3-fold increase in differentiated neurons (d9-d10; Figures 1B,C and Supplementary Figure S1), suggesting that the regulation of Drp1 levels could be a key event during neuronal differentiation
Neurons require high levels of energy for survival and for their specialized functions. These highly polarized cells are vulnerable to mitochondrial fission and fusion defects that lead to deficient cell bioenergetics and incorrect distribution of mitochondria along the axons and at the synapses

Summary

Introduction

Mitochondrial dynamics and the balance between fusion and fission are key adaptative mechanisms to the metabolic needs of the cell (Gomes et al, 2011; Schrepfer and Scorrano, 2016). Mitochondria are directly involved in differentiation and developmental processes (Kasahara and Scorrano, 2014). Mitochondria morphology, distribution and function are regulated by fusion and fission in response to the cellular environment and differentiation (Chang et al, 2006; Saxton and Hollenbeck, 2012). Drp acts as a cytosolic receptor, linking fission and mitochondrial function to the cytoplasmic state of the cell. For instance changes in cytosolic Ca2+ levels activates the Ca2+-dependent phosphatase calcineurin enhancing Drp dephosphorylation on Ser637 and its translocation to mitochondria (Cereghetti et al, 2008). Cyclic AMP activates protein kinase A (PKA), resulting in inhibitory phosphorylation of Ser637 that blocks Drp translocation and promotes mitochondrial elongation (Cribbs and Strack, 2007)

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Conclusion