KB-R7943, a Plasma Membrane Na(+)/Ca(2+) Exchanger Inhibitor, Blocks Opening of the Mitochondrial Permeability Transition Pore

Biochem Biophys Res Commun. 2014 Jan 31;444(1):44-9. doi: 10.1016/j.bbrc.2014.01.009. Epub 2014 Jan 14.

Abstract

The isothiourea derivative, KB-R7943, inhibits the reverse-mode of the plasma membrane sodium/calcium exchanger and protects against ischemia/reperfusion injury. The mechanism through which KB-R7943 confers protection, however, remains controversial. Recently, KB-R7943 has been shown to inhibit mitochondrial calcium uptake and matrix overload, which may contribute to its protective effects. While using KB-R7943 for this purpose, we find here no evidence that KB-R7943 directly blocks mitochondrial calcium uptake. Rather, we find that KB-R7943 inhibits opening of the mitochondrial permeability transition pore in permeabilized cells and isolated liver mitochondria. Furthermore, we find that this observation correlates with protection against calcium ionophore-induced mitochondrial membrane potential depolarization and cell death, without detrimental effects to basal mitochondrial membrane potential or complex I-dependent mitochondrial respiration. Our data reveal another mechanism through which KB-R7943 may protect against calcium-induced injury, as well as a novel means to inhibit the mitochondrial permeability transition pore.

Keywords: Calcium retention capacity; KB-R7943; Mitochondria; Permeability transition.

Publication types

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

MeSH terms

  • Animals
  • Calcium / metabolism
  • Calcium Channels / drug effects
  • Cell Death / drug effects
  • Cell Line
  • HeLa Cells
  • Humans
  • Membrane Potential, Mitochondrial / drug effects
  • Mice
  • Mitochondria, Liver / drug effects
  • Mitochondria, Liver / metabolism
  • Mitochondrial Membrane Transport Proteins / drug effects*
  • Mitochondrial Membrane Transport Proteins / metabolism
  • Oxygen Consumption / drug effects
  • Sodium-Calcium Exchanger / antagonists & inhibitors*
  • Thiourea / analogs & derivatives*
  • Thiourea / pharmacology

Substances

  • 2-(2-(4-(4-nitrobenzyloxy)phenyl)ethyl)isothiourea methanesulfonate
  • Calcium Channels
  • Mitochondrial Membrane Transport Proteins
  • Sodium-Calcium Exchanger
  • mitochondrial calcium uniporter
  • mitochondrial permeability transition pore
  • Thiourea
  • Calcium