Glucose restriction drives spatial reorganization of mevalonate metabolism.
Glucose restriction drives spatial reorganization of mevalonate metabolism.
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DOI：
10.7554/elife.62591
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发表时间：
2021-04-07
期刊：
影响因子：
7.7
通讯作者：
Henne WM
中科院分区：
文献类型：
--
作者：
Rogers S;Hariri H;Wood NE;Speer NO;Henne WM
真核生物将代谢途径划分为亚细胞区域，但细胞器间接触在组织代谢反应中的作用仍然知之甚少。在这里，我们发现，在响应急性葡萄糖限制（AGR）时，酵母会进行甲羟戊酸途径的代谢重塑，该途径在核-液泡连接（NVJs）处进行空间协调。NVJ通过选择性保留HMG-CoA还原酶（HMGCRs）作为代谢平台，以upc2依赖的方式驱动甲羟戊酸途径通量。在AGR期间，hmgcr的空间滞留和甲羟戊酸途径通量的增加都依赖于nvjtether Nvj1。此外，我们证明了在AGR过程中，hmgcr以nvj1依赖的方式结合成高分子量的组装体。nvj1介导的HMGCR分配损失可以通过人工多聚HMGCR来绕过，这表明NVJ区隔化通过促进HMGCR在高分子量组装体中的关联来增强甲羟戊酸途径通量。HMGCR区隔化的缺失会干扰葡萄糖饥饿后的酵母生长，表明它促进了适应性代谢重塑。总的来说，我们提出了一种非规范的机制，通过在细胞器间接触部位限速的HMGCR酶的空间区隔来调节甲羟戊酸代谢。
Eukaryotes compartmentalize metabolic pathways into sub-cellular domains, but the role of inter-organelle contacts in organizing metabolic reactions remains poorly understood. Here, we show that in response to acute glucose restriction (AGR) yeast undergo metabolic remodeling of their mevalonate pathway that is spatially coordinated at nucleus-vacuole junctions (NVJs). The NVJ serves as a metabolic platform by selectively retaining HMG-CoA Reductases (HMGCRs), driving mevalonate pathway flux in an Upc2-dependent manner. Both spatial retention of HMGCRs and increased mevalonate pathway flux during AGR is dependent on NVJ tether Nvj1. Furthermore, we demonstrate that HMGCRs associate into high-molecular-weight assemblies during AGR in an Nvj1-dependent manner. Loss of Nvj1-mediated HMGCR partitioning can be bypassed by artificially multimerizing HMGCRs, indicating NVJ compartmentalization enhances mevalonate pathway flux by promoting the association of HMGCRs in high molecular weight assemblies. Loss of HMGCR compartmentalization perturbs yeast growth following glucose starvation, indicating it promotes adaptive metabolic remodeling. Collectively, we propose a non-canonical mechanism regulating mevalonate metabolism via the spatial compartmentalization of rate-limiting HMGCR enzymes at an inter-organelle contact site.