Human-Specific ARHGAP11B Acts in Mitochondria to Expand Neocortical Progenitors by Glutaminolysis.
3T3 Cells
Animals
Biological Evolution
Cell Proliferation
/ genetics
Citric Acid Cycle
GTPase-Activating Proteins
/ genetics
Gene Expression Regulation, Developmental
/ genetics
Glutamic Acid
/ metabolism
Glutamine
/ metabolism
Humans
Mice
Mitochondria
/ metabolism
Mitochondrial ADP, ATP Translocases
/ metabolism
Mitochondrial Membrane Transport Proteins
/ metabolism
Mitochondrial Permeability Transition Pore
Neocortex
/ embryology
Neural Stem Cells
/ metabolism
Neurogenesis
/ genetics
evolution
metabolism
neocortex
neural progenitor cells
Journal
Neuron
ISSN: 1097-4199
Titre abrégé: Neuron
Pays: United States
ID NLM: 8809320
Informations de publication
Date de publication:
04 03 2020
04 03 2020
Historique:
received:
27
06
2019
revised:
28
10
2019
accepted:
25
11
2019
pubmed:
31
12
2019
medline:
8
7
2020
entrez:
30
12
2019
Statut:
ppublish
Résumé
The human-specific gene ARHGAP11B is preferentially expressed in neural progenitors of fetal human neocortex and increases abundance and proliferation of basal progenitors (BPs), which have a key role in neocortex expansion. ARHGAP11B has therefore been implicated in the evolutionary expansion of the human neocortex, but its mode of action has been unknown. Here, we show that ARHGAP11B is imported into mitochondria, where it interacts with the adenine nucleotide translocase (ANT) and inhibits the mitochondrial permeability transition pore (mPTP). BP expansion by ARHGAP11B requires its presence in mitochondria, and pharmacological inhibition of ANT function or mPTP opening mimic BP expansion by ARHGAP11B. Searching for the underlying metabolic basis, we find that BP expansion by ARHGAP11B requires glutaminolysis, the conversion of glutamine to glutamate for the tricarboxylic acid (TCA) cycle. Hence, an ARHGAP11B-induced, mitochondria-based effect on BP metabolism that is a hallmark of highly mitotically active cells appears to underlie its role in neocortex expansion.
Identifiants
pubmed: 31883789
pii: S0896-6273(19)31036-0
doi: 10.1016/j.neuron.2019.11.027
pii:
doi:
Substances chimiques
ARHGAP11B protein, human
0
GTPase-Activating Proteins
0
Mitochondrial Membrane Transport Proteins
0
Mitochondrial Permeability Transition Pore
0
Glutamine
0RH81L854J
Glutamic Acid
3KX376GY7L
Mitochondrial ADP, ATP Translocases
9068-80-8
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
867-881.e9Subventions
Organisme : Medical Research Council
ID : MR/R006237/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/S025065/1
Pays : United Kingdom
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2019 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Interests The authors declare no competing interests.