Inorganic polyphosphate is required for sustained free mitochondrial calcium elevation, following calcium uptake

Cell Calcium. 2020 Mar:86:102127. doi: 10.1016/j.ceca.2019.102127. Epub 2019 Dec 9.


Mitochondrial free calcium is critically linked to the regulation of cellular metabolism. Free ionic calcium concentration within these organelles is determined by the interplay between two processes: exchange across the mitochondrial inner membrane and calcium-buffering within the matrix. During stimulated calcium uptake, calcium is primarily buffered by orthophosphate, preventing calcium toxicity while allowing for well-regulated yet elevated calcium loads. However, if limited to orthophosphates only, this buffering system is expected to lead to the irreversible formation of insoluble precipitates, which are not observed in living cells, under physiological conditions. Here, we demonstrate that the regulation of free mitochondrial calcium requires the presence of free inorganic polyphosphate (polyP) within the organelle. We found that the overexpression of a mitochondrial-targeted enzyme hydrolyzing polyP leads to the loss of the cellular ability to maintain elevated calcium concentrations within the organelle, following stimulated cytoplasmic signal. We hypothesize that the presence of polyP prevents the formation of calcium-phosphate insoluble clusters, allowing for the maintenance of elevated free calcium levels, during stimulated calcium uptake.

Keywords: Calcium homeostasis; Free calcium; Inorganic polyphosphate; Mitochondria; Orthophosphate; polyP.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / pharmacology
  • Benzoates / metabolism
  • Bridged Bicyclo Compounds / metabolism
  • Calcium / metabolism*
  • Calcium Signaling / drug effects
  • Cell Membrane Permeability / drug effects
  • Cycloheptanes / metabolism
  • HEK293 Cells
  • Humans
  • Membrane Potential, Mitochondrial / drug effects
  • Mitochondria / drug effects
  • Mitochondria / metabolism*
  • Models, Biological
  • Polyphosphates / pharmacology*
  • Ruthenium Red / metabolism
  • Sesquiterpenes / metabolism


  • Benzoates
  • Bridged Bicyclo Compounds
  • Cycloheptanes
  • Polyphosphates
  • Sesquiterpenes
  • Ruthenium Red
  • 4-oxy-6-(4-oxybezoyloxy)dauc-8,9-en
  • Adenosine Triphosphate
  • Calcium