Cyclosporin A increases resting mitochondrial membrane potential in SY5Y cells and reverses the depressed mitochondrial membrane potential of Alzheimer's disease cybrids

Biochem Biophys Res Commun. 1998 Jul 9;248(1):168-73. doi: 10.1006/bbrc.1998.8866.


Alzheimer's disease (AD) brains exhibit oxidative stress and a biochemical defect of complex IV (cytochrome oxidase, COX) of the mitochondrial electron transport chain (ETC). This defect can be transferred through mitochondrial DNA (mtDNA) into clonal SY5Y cells depleted of their mtDNA. The resulting cytoplasmic hybrids or "cybrids" retain the complex IV defect and exhibit oxidative stress. We measured the mitochondrial membrane potential (delta psi m) in AD and control cybrids via H3-tetraphenylphosphonium ion (H3-TPP+) accumulation. AD cybrids exhibited a significant (about 30%) decrease in H3-TPP+ accumulation relative to controls. Acute treatment of normal SY5Ys with azide, a COX inhibitor, moderately decreased H3-TPP+ retention and strongly inhibited COX activity in a dose-dependent manner. As the mitochondrial transition pore (MTP) can be activated by reactive oxygen species and ETC inhibitors, and its opening causes delta psi m dissipation, we tested the effects of the MTP inhibitor cyclosporin A (CsA) on TPP+ accumulation. 5mM CsA increased basal H3-TPP+ accumulation in SY5Y cells about 10-fold, corresponding to about a 2-fold increase in delta psi m. In the AD cybrids, CsA increased the apparent delta psi m to the same final levels as it did in controls. These results indicate that low-conductance MTP activity contributes significantly to resting delta psi m in SY5Y cells. We propose the novel hypothesis that the COX defect and resulting oxidative stress in AD may pathologically activate the MTP, resulting in lower delta psi m and the release of mitochondrial factors involved in apoptosis.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alzheimer Disease / genetics
  • Alzheimer Disease / physiopathology*
  • Atractyloside / pharmacology
  • Carbonyl Cyanide m-Chlorophenyl Hydrazone / pharmacology
  • Cyclosporine / pharmacology*
  • DNA, Mitochondrial / genetics
  • Electron Transport Complex IV / antagonists & inhibitors
  • Electron Transport Complex IV / metabolism
  • Humans
  • Intracellular Membranes / drug effects
  • Intracellular Membranes / physiology*
  • Membrane Potentials / drug effects
  • Mitochondria / drug effects
  • Mitochondria / physiology*
  • Monoamine Oxidase / metabolism
  • Onium Compounds / metabolism
  • Organophosphorus Compounds / metabolism
  • Sodium Azide / pharmacology
  • Tumor Cells, Cultured


  • DNA, Mitochondrial
  • Onium Compounds
  • Organophosphorus Compounds
  • Atractyloside
  • Carbonyl Cyanide m-Chlorophenyl Hydrazone
  • Cyclosporine
  • Sodium Azide
  • Monoamine Oxidase
  • Electron Transport Complex IV
  • tetraphenylphosphonium