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/metabolism; 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/metabolism; Neural Stem Cells/metabolism; Neurogenesis/genetics; evolution; metabolism; neocortex; neural progenitor cells

Abstract :

[en] 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.

Disciplines :

Neurology

Author, co-author :

Namba, Takashi

Dóczi, Judit

Pinson, Anneline ; Université de Liège - ULiège

Xing, Lei

Kalebic, Nereo

Wilsch-Bräuninger, Michaela

Long, Katherine R.

Vaid, Samir

Lauer, Janelle

Bogdanova, Aliona

More authors (8 more)

Language :

English

Title :

Human-Specific ARHGAP11B Acts in Mitochondria to Expand Neocortical Progenitors by Glutaminolysis.

Publication date :

2020

Journal title :

Neuron

ISSN :

0896-6273

eISSN :

1097-4199

Publisher :

Cell Press, Cambridge, United States - Massachusetts

Volume :

105

Issue :

Pages :

867-881.e9

Peer reviewed :

Peer Reviewed verified by ORBi

Commentary :

Available on ORBi :

since 16 January 2021

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4 (3 by ULiège)

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Scopus citations^®

102

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OpenCitations

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124

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