Mitochondrial Calcium Signalling and Cell Death: Approaches for Assessing the Role of Mitochondrial Ca2+ Uptake in Apoptosis

Cell Calcium. Nov-Dec 2006;40(5-6):553-60. doi: 10.1016/j.ceca.2006.08.016. Epub 2006 Oct 30.

Abstract

Local Ca(2+) transfer between adjoining domains of the sarcoendoplasmic reticulum (ER/SR) and mitochondria allows ER/SR Ca(2+) release to activate mitochondrial Ca(2+) uptake and to evoke a matrix [Ca(2+)] ([Ca(2+)](m)) rise. [Ca(2+)](m) exerts control on several steps of energy metabolism to synchronize ATP generation with cell function. However, calcium signal propagation to the mitochondria may also ignite a cell death program through opening of the permeability transition pore (PTP). This occurs when the Ca(2+) release from the ER/SR is enhanced or is coincident with sensitization of the PTP. Recent studies have shown that several pro-apoptotic factors, including members of the Bcl-2 family proteins and reactive oxygen species (ROS) regulate the Ca(2+) sensitivity of both the Ca(2+) release channels in the ER and the PTP in the mitochondria. To test the relevance of the mitochondrial Ca(2+) accumulation in various apoptotic paradigms, methods are available for buffering of [Ca(2+)], for dissipation of the driving force of the mitochondrial Ca(2+) uptake and for inhibition of the mitochondrial Ca(2+) transport mechanisms. However, in intact cells, the efficacy and the specificity of these approaches have to be established. Here we discuss mechanisms that recruit the mitochondrial calcium signal to a pro-apoptotic cascade and the approaches available for assessment of the relevance of the mitochondrial Ca(2+) handling in apoptosis. We also present a systematic evaluation of the effect of ruthenium red and Ru360, two inhibitors of mitochondrial Ca(2+) uptake on cytosolic [Ca(2+)] and [Ca(2+)](m) in intact cultured cells.

Publication types

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

MeSH terms

  • Animals
  • Apoptosis / physiology*
  • Calcium / metabolism*
  • Calcium Channels / drug effects
  • Calcium Channels / metabolism
  • Calcium Signaling / physiology*
  • Endoplasmic Reticulum / metabolism
  • Mitochondria / physiology*
  • Mitochondrial Membrane Transport Proteins / metabolism
  • Sarcoplasmic Reticulum / metabolism

Substances

  • Calcium Channels
  • Mitochondrial Membrane Transport Proteins
  • mitochondrial calcium uniporter
  • mitochondrial permeability transition pore
  • Calcium