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

Andrey Y. Abramov, Cresson Fraley, Catherine T. Diao, Robert Winkfein, Michael A. Colicos, Michael R. Duchen, Robert J. French, Evgeny Pavlov

Research output: Contribution to journalArticle

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 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.

Original languageEnglish (US)
Pages (from-to)18091-18096
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number46
DOIs
StatePublished - Nov 13 2007

Fingerprint

endopolyphosphatase
Polyphosphates
Cell Death
Calcium
Energy Metabolism
Ion Transport
Amyloid
NAD
Membrane Potentials
Permeability
Alzheimer Disease
Mitochondria
Adenosine Triphosphate
Phosphates

Keywords

  • β-amyloid peptide
  • Mitochondria
  • Necrosis
  • Permeability transition
  • Polyphosphate

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Targeted polyphosphatase expression alters mitochondrial metabolism and inhibits calcium-dependent cell death. / Abramov, Andrey Y.; Fraley, Cresson; Diao, Catherine T.; Winkfein, Robert; Colicos, Michael A.; Duchen, Michael R.; French, Robert J.; Pavlov, Evgeny.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 104, No. 46, 13.11.2007, p. 18091-18096.

Research output: Contribution to journalArticle

Abramov, Andrey Y. ; Fraley, Cresson ; Diao, Catherine T. ; Winkfein, Robert ; Colicos, Michael A. ; Duchen, Michael R. ; French, Robert J. ; Pavlov, Evgeny. / Targeted polyphosphatase expression alters mitochondrial metabolism and inhibits calcium-dependent cell death. In: Proceedings of the National Academy of Sciences of the United States of America. 2007 ; Vol. 104, No. 46. pp. 18091-18096.
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AU - Abramov, Andrey Y.

AU - Fraley, Cresson

AU - Diao, Catherine T.

AU - Winkfein, Robert

AU - Colicos, Michael A.

AU - Duchen, Michael R.

AU - French, Robert J.

AU - Pavlov, Evgeny

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N2 - 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.

AB - 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.

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KW - Necrosis

KW - Permeability transition

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