通过抑制线粒体丙酮酸输入唤醒神经干细胞

Brain-X Pub Date : 2023-05-29 DOI:10.1002/brx2.13
Yajiao Shi, You Wan, Jie Zheng
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引用次数: 0

摘要

神经发生在成年后急剧下降,部分原因是神经干细胞和祖细胞(NSPCs)随着年龄的增长越来越多地恢复到休眠状态。然而,天生的NSPC池在个体一生中都保存在特定的大脑区域。Petrelli等人1最近报道,抑制线粒体丙酮酸盐输入刺激NSPCs从静止状态转变为活跃状态,从而促进年轻和中年小鼠的神经发生。这些发现表明了一种新的神经原性治疗方法。大脑中的大多数神经发生都是在胚胎发育过程中完成的,只有少量的NSPC在出生后产生新的神经元。这些NSPCs主要存在于海马齿状回和室下区。这种生物过程,特别是成年海马神经发生(AHN),在模式分离、学习记忆和情绪调节等特定功能中发挥着至关重要的作用。成人大脑中的NSPCs库逐渐减少,但由于神经干细胞在对称细胞分裂过程中的自我更新,在一生中保持在一定水平。然而,与NSC库的年龄依赖性耗竭相比,AHN的程度下降得更为剧烈。这种下降的最重要原因之一是成年大脑中NSCs从活跃状态转变为休眠状态、保持静止并拒绝增殖以启动神经发生的速率增加。因此,激活这些休眠的静止神经干细胞对于恢复神经发生至关重要。线粒体内膜上的线粒体丙酮酸载体(MPC)负责将糖酵解最终产物丙酮酸从胞质溶胶运输到线粒体中,从而将糖酵分解与三羧酸循环和氧化磷酸化联系起来。鉴于糖酵解在决定NSCs的活性状态中起着关键作用,Petrelli等人1最近发现,与活跃或增殖的NSPCs相比,MPC在静止的NSPCs中表达最高。此外,使用特异性膜穿透抑制剂UK5099在体外对MPC进行药理学阻断和选择性缺失NSPCs中的Mpc1基因都导致了这些静止的NSPCs的增殖。随后,作者旨在研究潜在的代谢机制。他们排除了MPC功能丧失导致乳酸升高的原因,因为补充乳酸或下调都不会影响NSPCs的增殖。相反,他们发现细胞内天冬氨酸升高,推测是由于谷氨酸-草酰乙酸转氨酶活性上调或线粒体天冬氨酸输入增强,在激活静止的NSPCs中发挥了重要作用。与静止的NSPCs相比,抑制MPC不影响已经活跃的NSPCs的增殖或其后代的分化。最后,作者证明,在一个月大的小鼠中,NSPCs中的条件Mpc1缺失增加了新产生的神经元的数量,而不影响轴突分化。重要的是,在NSPCs中条件性Mpc1缺失的中年小鼠(9-11个月大)中也观察到新形成神经元的数量增加(图1)。这项重要研究揭示了线粒体丙酮酸代谢在调节NSPCs静止和激活之间的平衡中的关键作用。它还激发了人们对探索新陈代谢与干细胞生物学之间关系的兴趣,包括神经科学、癌症研究和组织工程等各个学科。已经观察到,小鼠大脑中的总丙酮酸脱氢酶复合物随着年龄的增长而增加。2然而,由于丙酮酸参与的氧化活性和葡萄糖代谢对人类和小鼠的神经元发育时间有不同的影响,3需要进一步研究MPC抑制是否也能促进人类的NSPC激活和神经发生。另一个需要考虑的问题是,通过丙酮酸代谢紊乱来强制激活静止的NSPC是否会改变NSPC子代的命运,将其从神经发生转变为星形胶质细胞增生,或者导致成年NSC库的加速耗竭。研究发现,这可能导致神经发生的暂时增加,但最终会导致长期缺陷。4尽管存在许多挑战,但神经发生靶向治疗,无论是通过促进先天神经发生还是移植外源性干细胞,在恢复衰老的大脑和治疗以神经元丧失或神经退行性变为特征的神经系统疾病方面仍然具有巨大的潜力。 5考虑到丙酮酸代谢在NSPCs中启动神经发生的关键作用,MPC抑制剂,无论是单独给药还是与干细胞移植联合给药,都可能代表神经损伤和神经退行性疾病的新疗法。亚焦石和郑洁构思并撰写了手稿。游婉修改了论文。提交人声明他们没有利益冲突。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Waking up neural stem cells through inhibition of mitochondrial pyruvate import

Waking up neural stem cells through inhibition of mitochondrial pyruvate import

Neurogenesis declines sharply in adulthood, partly because neural stem and progenitor cells (NSPCs) increasingly return to a dormant state as they age. However, innate NSPC pools are preserved in specific brain regions throughout an individual's lifetime. Petrelli et al.1 recently reported that inhibiting mitochondrial pyruvate import stimulated NSPCs to transition from a quiescent state to an active state, thereby promoting neurogenesis in both young and middle-aged mice. These findings indicate a novel approach for pro-neurogenic treatments.

Most neurogenesis in the brain is completed during embryonic development, with only small pools of NSPCs remaining to generate new neurons postnatally. These NSPCs are primarily found in the hippocampal dentate gyrus and the subventricular zone. This biological process, particularly adult hippocampal neurogenesis (AHN), plays a crucial role in specific functions such as pattern separation, learning and memory, and emotional regulation. The pool of NSPCs in the adult brain gradually diminishes but is maintained at a certain level throughout life due to the self-renewal of neural stem cells during symmetric cell division.

However, the extent of AHN declines much more sharply compared with the age-dependent depletion of the NSC pool. One of the most significant causes for this decline is the increasing rate at which NSCs in the adult brain transition from an active to a dormant state, remaining quiescent and refusing to proliferate to initiate neurogenesis. Thus, activating these dormant quiescent NSCs is pivotal for restoring neurogenesis.

The mitochondrial pyruvate carrier (MPC) on the inner mitochondrial membrane is responsible for transporting the glycolytic end-product pyruvate from the cytosol into the mitochondria, thereby linking glycolysis to the tricarboxylic acid cycle and oxidative phosphorylation. Given that glycolysis plays a critical role in determining the activity state of NSCs, Petrelli et al.1 recently found that MPC expression was highest in quiescent NSPCs, as opposed to those that were active or proliferating.

Moreover, both pharmacological blockage of MPC in vitro using the specific membrane-penetrating inhibitor UK5099 and selective deletion of the Mpc1 gene in NSPCs led to the proliferation of these quiescent NSPCs. Subsequently, the authors aimed to investigate the underlying metabolic mechanism. They ruled out the contribution of lactate elevation resulting from MPC loss-of-function as neither lactate supplementation nor downregulation affected the proliferation of NSPCs.

Instead, they discovered that the elevated intracellular aspartate, presumed to be due to the upregulation of glutamic-oxaloacetic transaminase activity or enhanced mitochondrial aspartate import, played a significant role in activating quiescent NSPCs. In contrast to quiescent NSPCs, inhibiting MPCs did not affect the proliferation of already active NSPCs or the differentiation of their progeny.

Lastly, the authors demonstrated that conditional Mpc1 deletion in NSPCs increased the number of newly generated neurons without affecting the neurite differentiation in one-month-old mice. Importantly, an increase in the number of newly formed neurons was also observed in middle-aged mice (9–11 months of age) with conditional Mpc1 deletion in NSPCs (Figure 1).

This important study sheds light on the critical role of mitochondrial pyruvate metabolism in regulating the balance between quiescence and activation in NSPCs. It also sparks increased interest in exploring the relationship between metabolism and stem cell biology across various disciplines, including neuroscience, cancer research, and tissue engineering.

It has been observed that the total pyruvate dehydrogenase complex increases with age in mice brains.2 However, since pyruvate-involved oxidative activity and glucose metabolism have different effects on neuronal developmental timing in humans and mice,3 it warrants further investigation to determine whether MPC inhibition can also facilitate NSPC activation and neurogenesis in humans. Another question to consider is whether the forced activation of quiescent NSPCs through disrupted pyruvate metabolism might alter the fate of NSPC progeny, shifting them from neurogenesis to astrogliosis, or leading to the accelerated depletion of the adult NSC pool. It has been found that this can result in a temporary increase but ultimately long-term deficits in neurogenesis.4

Although there are numerous challenges, neurogenesis-targeted therapies, either by facilitating innate neurogenesis or engrafting exogenous stem cells, still hold great potential for rejuvenating aging brains and treating neurological disorders characterized by neuron loss or neurodegeneration.5 Considering the critical role of pyruvate metabolism in NSPCs for initiating neurogenesis, MPC inhibitors, whether administered alone or in combination with stem cell transplantation, could represent novel therapies for neurological injuries and neurodegenerative diseases.

Yajiao Shi and Jie Zheng conceptualized and wrote the manuscript. You Wan revised the paper.

The authors declare that they have no conflicts of interest.

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