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

Abramov, AY; Fraley, C; Diao, CT; Winkfein, R; Colicos, MA; Duchen, MR; French, RJ; (2007) Targeted polyphosphatase expression alters mitochondrial metabolism and inhibits calcium-dependent cell death. P NATL ACAD SCI USA , 104 (46) 18091 - 18096. 10.1073/pnas.0708959104. Gold open access

Abstract

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.

Type: Article
Title: Targeted polyphosphatase expression alters mitochondrial metabolism and inhibits calcium-dependent cell death
Open access status: An open access publication
DOI: 10.1073/pnas.0708959104
Publisher version: http://www.ncbi.nlm.nih.gov/pmc/ articles/PMC20843...
Keywords: mitochondria, permeability transition, polyphosphate, ss-amyloid peptide, necrosis, PERMEABILITY TRANSITION PORE, INORGANIC POLYPHOSPHATE, ESCHERICHIA-COLI, OXIDATIVE STRESS, NADPH OXIDASE, BETA PEPTIDES, IN-VITRO, NEUROTOXICITY, ASTROCYTES, MEMBRANES
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Movement Neurosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Cell and Developmental Biology
URI: http://discovery.ucl.ac.uk/id/eprint/151897
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