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

1 Citation (Scopus)

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
JournalFrontiers in Cellular Neuroscience
Volume13
DOIs
Publication statusPublished - Jan 29 2019

Fingerprint

Autophagy
Dynamins
Mitochondria
Apoptosis
Proteins
Mitochondrial Dynamics
Unfolded Protein Response
Huntington Disease
Amyotrophic Lateral Sclerosis
Tretinoin
Neurodegenerative Diseases
Parkinson Disease
Alzheimer Disease
Cell Death
Neurons

Keywords

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

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

Cite this

The fine tuning of drp1-dependent mitochondrial remodeling and autophagy controls neuronal differentiation. / Vantaggiato, Chiara; Castelli, Marianna; Giovarelli, Matteo; Orso, Genny; Bassi, Maria Teresa; Clementi, Emilio; De Palma, Clara.

In: Frontiers in Cellular Neuroscience, Vol. 13, 120, 29.01.2019.

Research output: Contribution to journalArticle

@article{c04d62382ffc425bab7ed954263dbf92,
title = "The fine tuning of drp1-dependent mitochondrial remodeling and autophagy controls neuronal differentiation",
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.",
keywords = "Autophagy, Drp1, Mitochondrial fission, Mitochondrial remodeling, Neuronal differentiation",
author = "Chiara Vantaggiato and Marianna Castelli and Matteo Giovarelli and Genny Orso and Bassi, {Maria Teresa} and Emilio Clementi and {De Palma}, Clara",
year = "2019",
month = "1",
day = "29",
doi = "10.3389/fncel.2019.00120",
language = "English",
volume = "13",
journal = "Frontiers in Cellular Neuroscience",
issn = "1662-5102",
publisher = "Frontiers Media S.A.",

}

TY - JOUR

T1 - The fine tuning of drp1-dependent mitochondrial remodeling and autophagy controls neuronal differentiation

AU - Vantaggiato, Chiara

AU - Castelli, Marianna

AU - Giovarelli, Matteo

AU - Orso, Genny

AU - Bassi, Maria Teresa

AU - Clementi, Emilio

AU - De Palma, Clara

PY - 2019/1/29

Y1 - 2019/1/29

N2 - 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.

AB - 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.

KW - Autophagy

KW - Drp1

KW - Mitochondrial fission

KW - Mitochondrial remodeling

KW - Neuronal differentiation

UR - http://www.scopus.com/inward/record.url?scp=85064220453&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85064220453&partnerID=8YFLogxK

U2 - 10.3389/fncel.2019.00120

DO - 10.3389/fncel.2019.00120

M3 - Article

VL - 13

JO - Frontiers in Cellular Neuroscience

JF - Frontiers in Cellular Neuroscience

SN - 1662-5102

M1 - 120

ER -