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.

中文翻译：

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人类特异性 ARHGAP11B 作用于线粒体以通过谷氨酰胺分解扩大新皮质祖细胞。

人类特异性基因 ARHGAP11B 优先在胎儿人类新皮质的神经祖细胞中表达，并增加基底祖细胞 (BPs) 的丰度和增殖，这在新皮质扩张中起着关键作用。因此，ARHGAP11B 与人类新皮层的进化扩张有关，但其作用方式尚不清楚。在这里，我们表明 ARHGAP11B 被导入线粒体，在那里它与腺嘌呤核苷酸转位酶 (ANT) 相互作用并抑制线粒体通透性转换孔 (mPTP)。ARHGAP11B 的 BP 扩张需要它存在于线粒体中，并且药理学抑制 ANT 功能或 mPTP 开放模拟 ARHGAP11B 的 BP 扩张。寻找潜在的代谢基础，我们发现 ARHGAP11B 的 BP 扩展需要谷氨酰胺分解，在三羧酸 (TCA) 循环中将谷氨酰胺转化为谷氨酸。因此，ARHGAP11B 诱导的、基于线粒体的 BP 代谢效应是高度有丝分裂活跃细胞的标志，似乎是其在新皮质扩张中作用的基础。