Inorganic polyphosphate is a potent activator of the mitochondrial permeability transition pore in cardiac myocytes

Lea K. Seidlmayer, Maria R. Gomez-Garcia, Lothar A. Blatter, Evgeny Pavlov, Elena N. Dedkova

Research output: Contribution to journalArticle

Abstract

Mitochondrial dysfunction caused by excessive Ca 2+ accumulation is a major contributor to cardiac cell and tissue damage during myocardial infarction and ischemia-reperfusion injury (IRI). At the molecular level, mitochondrial dysfunction is induced by Ca 2+-dependent opening of the mitochondrial permeability transition pore (mPTP) in the inner mitochondrial membrane, which leads to the dissipation of mitochondrial membrane potential (ΔΨ m), disruption of adenosine triphosphate production, and ultimately cell death. Although the role of Ca 2+ for induction of mPTP opening is established, the exact molecular mechanism of this process is not understood. The aim of the present study was to test the hypothesis that the adverse effect of mitochondrial Ca 2+ accumulation is mediated by its interaction with inorganic polyphosphate (polyP), a polymer of orthophosphates linked by phosphoanhydride bonds. We found that cardiac mitochondria contained significant amounts (280 ± 60 pmol/mg of protein) of short-chain polyP with an average length of 25 orthophosphates. To test the role of polyP for mPTP activity, we investigated kinetics of Ca 2+ uptake and release, ΔΨ m and Ca 2+-induced mPTP opening in polyPdepleted mitochondria. polyP depletion was achieved by mitochondria-targeted expression of a polyP-hydrolyzing enzyme. Depletion of polyP in mitochondria of rabbit ventricular myocytes led to significant inhibition of mPTP opening without affecting mitochondrial Ca 2+ concentration by itself. This effect was observed when mitochondrial Ca 2+ uptake was stimulated by increasing cytosolic [Ca 2+] in permeabilized myocytes mimicking mitochondrial Ca 2+ overload observed during IRI. Our findings suggest that inorganic polyP is a previously unrecognized major activator of mPTP. We propose that the adverse effect of polyphosphate might be caused by its ability to form stable complexes with Ca 2+ and directly contribute to inner mitochondrial membrane permeabilization.

Original languageEnglish (US)
Pages (from-to)321-331
Number of pages11
JournalJournal of General Physiology
Volume139
Issue number5
DOIs
StatePublished - May 2012

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Polyphosphates
Cardiac Myocytes
Mitochondria
Mitochondrial Membranes
Reperfusion Injury
Muscle Cells
Phosphates
mitochondrial permeability transition pore
Mitochondrial Membrane Potential
Myocardial Ischemia
Polymers
Cell Death
Adenosine Triphosphate
Myocardial Infarction
Rabbits
Enzymes

ASJC Scopus subject areas

  • Physiology

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Inorganic polyphosphate is a potent activator of the mitochondrial permeability transition pore in cardiac myocytes. / Seidlmayer, Lea K.; Gomez-Garcia, Maria R.; Blatter, Lothar A.; Pavlov, Evgeny; Dedkova, Elena N.

In: Journal of General Physiology, Vol. 139, No. 5, 05.2012, p. 321-331.

Research output: Contribution to journalArticle

Seidlmayer, Lea K. ; Gomez-Garcia, Maria R. ; Blatter, Lothar A. ; Pavlov, Evgeny ; Dedkova, Elena N. / Inorganic polyphosphate is a potent activator of the mitochondrial permeability transition pore in cardiac myocytes. In: Journal of General Physiology. 2012 ; Vol. 139, No. 5. pp. 321-331.
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AB - Mitochondrial dysfunction caused by excessive Ca 2+ accumulation is a major contributor to cardiac cell and tissue damage during myocardial infarction and ischemia-reperfusion injury (IRI). At the molecular level, mitochondrial dysfunction is induced by Ca 2+-dependent opening of the mitochondrial permeability transition pore (mPTP) in the inner mitochondrial membrane, which leads to the dissipation of mitochondrial membrane potential (ΔΨ m), disruption of adenosine triphosphate production, and ultimately cell death. Although the role of Ca 2+ for induction of mPTP opening is established, the exact molecular mechanism of this process is not understood. The aim of the present study was to test the hypothesis that the adverse effect of mitochondrial Ca 2+ accumulation is mediated by its interaction with inorganic polyphosphate (polyP), a polymer of orthophosphates linked by phosphoanhydride bonds. We found that cardiac mitochondria contained significant amounts (280 ± 60 pmol/mg of protein) of short-chain polyP with an average length of 25 orthophosphates. To test the role of polyP for mPTP activity, we investigated kinetics of Ca 2+ uptake and release, ΔΨ m and Ca 2+-induced mPTP opening in polyPdepleted mitochondria. polyP depletion was achieved by mitochondria-targeted expression of a polyP-hydrolyzing enzyme. Depletion of polyP in mitochondria of rabbit ventricular myocytes led to significant inhibition of mPTP opening without affecting mitochondrial Ca 2+ concentration by itself. This effect was observed when mitochondrial Ca 2+ uptake was stimulated by increasing cytosolic [Ca 2+] in permeabilized myocytes mimicking mitochondrial Ca 2+ overload observed during IRI. Our findings suggest that inorganic polyP is a previously unrecognized major activator of mPTP. We propose that the adverse effect of polyphosphate might be caused by its ability to form stable complexes with Ca 2+ and directly contribute to inner mitochondrial membrane permeabilization.

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