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

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. •Human-specific ARHGAP11B is localized in mitochondria•ARHGAP11B interacts with ANT and inhibits mPTP•ARHGAP11B increases mitochondrial Ca2+ concentration and induces glutaminolysis•Glutaminolysis is required for human basal progenitor proliferation Namba et al. demonstrate that increased glutaminolysis is essential for the ability of human-specific ARHGAP11B, which is localized in mitochondria, to increase cycling basal progenitor levels in developing neocortex, an effect implicated in the evolutionary expansion of the human neocortex.