Contribution of inorganic polyphosphate towards regulation of mitochondrial free calcium

M. E. Solesio, L. Demirkhanyan, E. Zakharian, Evgeny Pavlov

Research output: Contribution to journalArticle

Abstract

Background: Calcium signaling plays a key role in the regulation of multiple processes in mammalian mitochondria, from cellular bioenergetics to the induction of stress-induced cell death. While the total concentration of calcium inside the mitochondria can increase by several orders of magnitude, the concentration of bioavailable free calcium in mitochondria is maintained within the micromolar range by the mitochondrial calcium buffering system. This calcium buffering system involves the participation of inorganic phosphate. However, the mechanisms of its function are not yet understood. Specifically, it is not clear how calcium-orthophosphate interactions, which normally lead to formation of insoluble precipitates, are capable to dynamically regulate free calcium concentration. Here we test the hypothesis that inorganic polyphosphate, which is a polymerized form of orthophosphate, is capable to from soluble complexes with calcium, playing a significant role in the regulation of the mitochondrial free calcium concentration. Methods: We used confocal fluorescence microscopy to measure the relative levels of mitochondrial free calcium in cultured hepatoma cells (HepG2) with variable levels of inorganic polyphosphate (polyP). Results: The depletion of polyP leads to the significantly lower levels of mitochondrial free calcium concentration under conditions of pathological calcium overload. These results are coherent with previous observations showing that inorganic polyphosphate (polyP) can inhibit calcium-phosphate precipitation and, thus, increase the amount of free calcium. Conclusions: Inorganic polyphosphate plays an important role in the regulation of mitochondrial free calcium, leading to its significant increase. General significance: Inorganic polyphosphate is a previously unrecognized integral component of the mitochondrial calcium buffering system.

Original languageEnglish (US)
Pages (from-to)1317-1325
Number of pages9
JournalBBA - General Subjects
Volume1860
Issue number6
DOIs
StatePublished - Jun 1 2016

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Polyphosphates
Calcium
Mitochondria
Phosphates
Calcium Signaling
Confocal microscopy
Fluorescence microscopy
Cell death
Fluorescence Microscopy
Confocal Microscopy
Energy Metabolism

Keywords

  • Calcium
  • Inorganic polyphosphate
  • Mitochondria
  • Polyphosphatase

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Molecular Biology

Cite this

Contribution of inorganic polyphosphate towards regulation of mitochondrial free calcium. / Solesio, M. E.; Demirkhanyan, L.; Zakharian, E.; Pavlov, Evgeny.

In: BBA - General Subjects, Vol. 1860, No. 6, 01.06.2016, p. 1317-1325.

Research output: Contribution to journalArticle

Solesio, M. E. ; Demirkhanyan, L. ; Zakharian, E. ; Pavlov, Evgeny. / Contribution of inorganic polyphosphate towards regulation of mitochondrial free calcium. In: BBA - General Subjects. 2016 ; Vol. 1860, No. 6. pp. 1317-1325.
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AB - Background: Calcium signaling plays a key role in the regulation of multiple processes in mammalian mitochondria, from cellular bioenergetics to the induction of stress-induced cell death. While the total concentration of calcium inside the mitochondria can increase by several orders of magnitude, the concentration of bioavailable free calcium in mitochondria is maintained within the micromolar range by the mitochondrial calcium buffering system. This calcium buffering system involves the participation of inorganic phosphate. However, the mechanisms of its function are not yet understood. Specifically, it is not clear how calcium-orthophosphate interactions, which normally lead to formation of insoluble precipitates, are capable to dynamically regulate free calcium concentration. Here we test the hypothesis that inorganic polyphosphate, which is a polymerized form of orthophosphate, is capable to from soluble complexes with calcium, playing a significant role in the regulation of the mitochondrial free calcium concentration. Methods: We used confocal fluorescence microscopy to measure the relative levels of mitochondrial free calcium in cultured hepatoma cells (HepG2) with variable levels of inorganic polyphosphate (polyP). Results: The depletion of polyP leads to the significantly lower levels of mitochondrial free calcium concentration under conditions of pathological calcium overload. These results are coherent with previous observations showing that inorganic polyphosphate (polyP) can inhibit calcium-phosphate precipitation and, thus, increase the amount of free calcium. Conclusions: Inorganic polyphosphate plays an important role in the regulation of mitochondrial free calcium, leading to its significant increase. General significance: Inorganic polyphosphate is a previously unrecognized integral component of the mitochondrial calcium buffering system.

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