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

Andrey Y. Abramov*Department of Physiology and Mitochondrial Biology Group, University College London, Gower Street, London WC1E 6BT, United Kingdom;Cresson D. FraleyDepartment of Biochemistry, Stanford University School of Medicine, 279 West Campus Drive, Stanford, CA 94305-5307;Catherine DiaoDepartment of Physiology and Biophysics, University of Calgary, 3330 Hospital Drive N.W., Calgary, AB, Canada T2N 4N1Robert J. WinkfeinDepartment of Physiology and Biophysics, University of Calgary, 3330 Hospital Drive N.W., Calgary, AB, Canada T2N 4N1Michael A. ColicosDepartment of Physiology and Biophysics, University of Calgary, 3330 Hospital Drive N.W., Calgary, AB, Canada T2N 4N1Michael R. Duchen*Department of Physiology and Mitochondrial Biology Group, University College London, Gower Street, London WC1E 6BT, United Kingdom;Robert J. FrenchDepartment of Physiology and Biophysics, University of Calgary, 3330 Hospital Drive N.W., Calgary, AB, Canada T2N 4N1Evgeny V. PavlovDepartment of Physiology and Biophysics, University of Calgary, 3330 Hospital Drive N.W., Calgary, AB, Canada T2N 4N1

2007en

ABI

Annotatsiya

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.

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Identifikatorlar

DOI: 10.1073/pnas.0708959104

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