Malonate Induces Cell Death via Mitochondrial Potential Collapse and Delayed Swelling Through an ROS-dependent Pathway

Br J Pharmacol. 2005 Feb;144(4):528-37. doi: 10.1038/sj.bjp.0706069.

Abstract

1. Herein we study the effects of the mitochondrial complex II inhibitor malonate on its primary target, the mitochondrion. 2. Malonate induces mitochondrial potential collapse, mitochondrial swelling, cytochrome c (Cyt c) release and depletes glutathione (GSH) and nicotinamide adenine dinucleotide coenzyme (NAD(P)H) stores in brain-isolated mitochondria. 3. Although, mitochondrial potential collapse was almost immediate after malonate addition, mitochondrial swelling was not evident before 15 min of drug presence. This latter effect was blocked by cyclosporin A (CSA), Ruthenium Red (RR), magnesium, catalase, GSH and vitamin E. 4. Malonate added to SH-SY5Y cell cultures produced a marked loss of cell viability together with the release of Cyt c and depletion of GSH and NAD(P)H concentrations. All these effects were not apparent in SH-SY5Y cells overexpressing Bcl-xL. 5. When GSH concentrations were lowered with buthionine sulphoximine, cytoprotection afforded by Bcl-xL overexpression was not evident anymore. 6. Taken together, all these data suggest that malonate causes a rapid mitochondrial potential collapse and reactive oxygen species production that overwhelms mitochondrial antioxidant capacity and leads to mitochondrial swelling. Further permeability transition pore opening and the subsequent release of proapoptotic factors such as Cyt c could therefore be, at least in part, responsible for malonate-induced toxicity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Death / drug effects
  • Cell Line
  • Cell Survival / drug effects
  • Cytochromes c / metabolism
  • DNA Fragmentation / drug effects
  • Glutathione / metabolism
  • Ion Channels / metabolism
  • Malonates / toxicity*
  • Mitochondria / drug effects*
  • Mitochondria / metabolism
  • Mitochondrial Membrane Transport Proteins
  • Mitochondrial Swelling / drug effects*
  • NADP / metabolism
  • Oxidation-Reduction
  • Prosencephalon / cytology
  • Proto-Oncogene Proteins c-bcl-2 / biosynthesis
  • Rats
  • Reactive Oxygen Species / metabolism*
  • bcl-X Protein

Substances

  • Bcl2l1 protein, rat
  • Ion Channels
  • Malonates
  • Mitochondrial Membrane Transport Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Reactive Oxygen Species
  • bcl-X Protein
  • mitochondrial permeability transition pore
  • NADP
  • Cytochromes c
  • malonic acid
  • Glutathione