Targeted polyphosphatase expression alters mitochondrial metabolism and inhibits calcium-dependent cell death
Targeted polyphosphatase expression alters mitochondrial metabolism and inhibits calcium-dependent cell death
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DOI：
10.1073/pnas.0708959104
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发表时间：
2007-11-13
影响因子：
11.1
通讯作者：
Pavlov, Evgeny
中科院分区：
文献类型：
--
作者：
Abramov, Andrey Y.;Fraley, Cresson;Pavlov, Evgeny
聚磷酸盐（polyP）由数十至数百个磷酸盐组成，通过类似ATP的高能键连接。虽然polyP存在于哺乳动物线粒体中，但其生理作用尚不清楚。在这里，我们研究参与线粒体能量代谢和离子转运的聚P。我们构建了一个载体来表达一个以细胞为靶点的多聚磷酸酶，沿着有一个GFP荧光标记。通过聚磷酸酶表达，线粒体聚P的特异性减少显着调节线粒体生物能量学，如内膜电位的降低和NADH水平的增加所示。此外，聚P水平的降低增加了线粒体积累钙的能力，并降低了钙诱导的线粒体渗透性转变的可能性，这是许多类型的坏死细胞死亡中的中心事件。这赋予了对细胞死亡的保护，包括由β-淀粉样肽（阿尔茨海默病的病原体）诱导的细胞死亡。这些结果证明了聚P在哺乳动物细胞的线粒体功能中发挥的关键作用。
Polyphosphate (polyP) consists of tens to hundreds of phosphates, linked by ATP-like high-energy bonds. Although polyP is present in mammalian mitochondria, its physiological roles there are obscure. Here, we examine the involvement of polyP in mitochondrial energy metabolism and ion transport. We constructed a vector to express a mitochondrially targeted polyphosphatase, along with a GFP fluorescent tag. Specific reduction of mitochondrial polyP, by polyphosphatase expression, significantly modulates mitochondrial bioenergetics, as indicated by the reduction of inner membrane potential and increased NADH levels. Furthermore, reduction of polyP levels increases mitochondrial capacity to accumulate calcium and reduces the likelihood of the calcium-induced mitochondrial permeability transition, a central event in many types of necrotic cell death. This confers protection against cell death, including that induced by beta-amyloid peptide, a pathogenic agent in Alzheimer's disease. These results demonstrate a crucial role played by polyP in mitochondrial function of mammalian cells.