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

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 c...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2007-11, Vol.104 (46), p.18091-18096
Main Authors: Abramov, Andrey Y, Fraley, Cresson, Diao, Catherine T, Winkfein, Robert, Colicos, Michael A, Duchen, Michael R, French, Robert J, Pavlov, Evgeny
Format: Article
Language:English
Subjects:
Acid Anhydride Hydrolases - metabolism
Adenosine Triphosphate - metabolism
Apoptosis
Astrocytes
Biological Sciences
Calcium
Calcium - metabolism
Cell Death
Cell Line
Cells
Depolarization
Energy Metabolism
Fluorescence
Gene expression
Green Fluorescent Proteins - metabolism
HEK293 cells
Hep G2 cells
Humans
Ion Transport
Ions
Membrane Potentials
Mitochondria
Mitochondria - enzymology
Mitochondria - metabolism
Mitochondrial membranes
NAD - metabolism
Neurons
Pathogens
Peptides
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Summary: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 β-amyloid peptide, a pathogenic agent in Alzheimer's disease. These results demonstrate a crucial role played by polyP in mitochondrial function of mammalian cells.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0708959104