Max Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstraße 108, 01307 Dresden, Germany.
Department of Medical Biochemistry, Semmelweis University, Budapest, Tuzolto St. 37-47 1094, Hungary.
Neuron. 2020 Mar 4;105(5):867-881.e9. doi: 10.1016/j.neuron.2019.11.027. Epub 2019 Dec 26.
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.
人类特异性基因 ARHGAP11B 在胎儿人类新皮质的神经祖细胞中优先表达，并增加基底祖细胞（BPs）的丰度和增殖，BPs 在新皮质扩张中起关键作用。因此，ARHGAP11B 被牵连到人类新皮质的进化扩张中，但它的作用模式尚不清楚。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易位酶（ANT）相互作用并抑制线粒体通透性转换孔（mPTP）。ARHGAP11B 通过 BPs 扩张需要其在线粒体中存在，并且 ANT 功能的药理学抑制或 mPTP 开口的打开模拟 ARHGAP11B 通过 BPs 扩张。为了寻找潜在的代谢基础，我们发现 ARHGAP11B 通过 BPs 扩张需要谷氨酰胺分解代谢，即谷氨酰胺转化为谷氨酸用于三羧酸（TCA）循环。因此，ARHGAP11B 诱导的、基于线粒体的对 BP 代谢的影响是高度有丝分裂活性细胞的标志，似乎是其在新皮质扩张中的作用基础。
