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.
