Depletion of mitochondrial inorganic polyphosphate (polyP) in mammalian cells causes metabolic shift from oxidative phosphorylation to glycolysis.
Depletion of mitochondrial inorganic polyphosphate (polyP) in mammalian cells causes metabolic shift from oxidative phosphorylation to glycolysis.
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DOI：
10.1042/bcj20200975
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发表时间：
2021-04-30
期刊：
影响因子：
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通讯作者：
Pavlov EV
中科院分区：
文献类型：
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作者：
Solesio ME;Xie L;McIntyre B;Ellenberger M;Mitaishvili E;Bhadra-Lobo S;Bettcher LF;Bazil JN;Raftery D;Jakob U;Pavlov EV
无机聚磷酸盐 (polyP) 是一种线性聚合物，由多达数百个正磷酸盐组成，这些正磷酸盐通过高能磷酸酐键连接在一起，与 ATP 中的键相同。在哺乳动物线粒体中，polyP 参与多种过程，包括能量代谢、离子通道功能和钙信号传导的调节。然而，polyP 在细胞器内的所有这些作用的具体机制仍然知之甚少。本研究的中心目标是研究线粒体polyP如何参与哺乳动物细胞能量代谢的调节。为了实现这一目标，我们通过稳定表达聚磷蛋白水解酶 (scPPX)，创建了去除线粒体聚磷蛋白的 HEK293 细胞。我们发现这些细胞的氧化磷酸化（OXPHOS）速率显着降低，而糖酵解速率则升高。与此一致的是，代谢组学测定证实与野生型样品相比，这些细胞中参与糖酵解的代谢物水平增加。同时，分离的线粒体的关键呼吸参数没有变化，表明呼吸链活性不受线粒体polyP缺乏的影响。然而，我们发现，与野生型细胞相比，缺乏线粒体多聚蛋白的细胞的线粒体更加破碎。基于这些结果，我们提出线粒体多聚磷酸作为 OXPHOS 和糖酵解之间代谢转换的调节剂发挥着重要作用。
Inorganic polyphosphate (polyP) is a linear polymer composed of up to a few hundred orthophosphates linked together by high-energy phosphoanhydride bonds, identical with those found in ATP. In mammalian mitochondria, polyP has been implicated in multiple processes, including energy metabolism, ion channels function, and the regulation of calcium signaling. However, the specific mechanisms of all these effects of polyP within the organelle remain poorly understood. The central goal of this study was to investigate how mitochondrial polyP participates in the regulation of the mammalian cellular energy metabolism. To accomplish this, we created HEK293 cells depleted of mitochondrial polyP, through the stable expression of the polyP hydrolyzing enzyme (scPPX). We found that these cells have significantly reduced rates of oxidative phosphorylation (OXPHOS), while their rates of glycolysis were elevated. Consistent with this, metabolomics assays confirmed increased levels of metabolites involved in glycolysis in these cells, compared with the wild-type samples. At the same time, key respiratory parameters of the isolated mitochondria were unchanged, suggesting that respiratory chain activity is not affected by the lack of mitochondrial polyP. However, we detected that mitochondria from cells that lack mitochondrial polyP are more fragmented when compared with those from wild-type cells. Based on these results, we propose that mitochondrial polyP plays an important role as a regulator of the metabolic switch between OXPHOS and glycolysis.