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 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.
Abramov
Andrey Y
AY
Department of Physiology and Mitochondrial Biology Group, University College London, Gower Street, London WC1E 6BT, United Kingdom.
Fraley
Cresson
C
Diao
Catherine T
CT
Winkfein
Robert
R
Colicos
Michael A
MA
Duchen
Michael R
MR
French
Robert J
RJ
Pavlov
Evgeny
E
D017766:Acid Anhydride Hydrolases / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D016923:Cell Death; D002460:Cell Line; D004734:Energy Metabolism; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D017136:Ion Transport; D008564:Membrane Potentials; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism*; D009243:NAD / Q000378:metabolism
D009243:NAD; D049452:Green Fluorescent Proteins; D000255:Adenosine Triphosphate; D017766:Acid Anhydride Hydrolases; C022563:endopolyphosphatase; D002118:Calcium