Targeted polyphosphatase expression alters mitochondrial metabolism and inhibits calcium-dependent cell death

被引:162
作者
Abramov, Andrey Y.
Fraley, Cresson
Diao, Catherine T.
Winkfein, Robert
Colicos, Michael A.
Duchen, Michael R.
French, Robert J.
Pavlov, Evgeny
机构
[1] Univ Calgary, Dept Phys & Biophys, Calgary, AB T2N 4N1, Canada
[2] Metis Biosci Inc, Santa Cruz, CA 95060 USA
[3] Stanford Univ, Sch Med, Dept Biochem, Stanford, CA 94305 USA
[4] UCL, Dept Physiol, London WC1E 6BT, England
[5] UCL, Mitochondrial Grp, London WC1E 6BT, England
基金
英国惠康基金;
关键词
mitochondria; permeability transition; polyphosphate; ss-amyloid peptide; necrosis;
D O I
10.1073/pnas.0708959104
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
收藏
页码:18091 / 18096
页数:6
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