Respiratory complex I dysfunction due to mitochondrial DNA mutations shifts the voltage threshold for opening of the permeability transition pore toward resting levels

J Biol Chem. 2009 Jan 23;284(4):2045-52. doi: 10.1074/jbc.M807321200. Epub 2008 Dec 1.


We have studied mitochondrial bioenergetics in HL180 cells (a cybrid line harboring the T14484C/ND6 and G14279A/ND6 mtDNA mutations of Leber hereditary optic neuropathy, leading to an approximately 50% decrease of ATP synthesis) and XTC.UC1 cells (derived from a thyroid oncocytoma bearing a disruptive frameshift mutation in MT-ND1, which impairs complex I assembly). The addition of rotenone to HL180 cells and of antimycin A to XTC.UC1 cells caused fast mitochondrial membrane depolarization that was prevented by treatment with cyclosporin A, intracellular Ca2+ chelators, and antioxidant. Both cell lines also displayed an anomalous response to oligomycin, with rapid onset of depolarization that was prevented by cyclosporin A and by overexpression of Bcl-2. These findings indicate that depolarization by respiratory chain inhibitors and oligomycin was due to opening of the mitochondrial permeability transition pore (PTP). A shift of the threshold voltage for PTP opening close to the resting potential may therefore be the underlying cause facilitating cell death in diseases affecting complex I activity. This study provides a unifying reading frame for previous observations on mitochondrial dysfunction, bioenergetic defects, and Ca2+ deregulation in mitochondrial diseases. Therapeutic strategies aimed at normalizing the PTP voltage threshold may be instrumental in ameliorating the course of complex I-dependent mitochondrial diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / biosynthesis
  • Biological Transport
  • Cell Line
  • Culture Media, Conditioned
  • DNA, Mitochondrial / genetics*
  • Electron Transport Complex I / genetics
  • Electron Transport Complex I / metabolism*
  • Galactose / metabolism
  • Glucose / metabolism
  • Mitochondria / drug effects
  • Mitochondria / genetics
  • Mitochondria / metabolism
  • Mitochondrial Membranes
  • Mutation / genetics
  • Oligomycins / pharmacology
  • Oxygen Consumption
  • Permeability
  • Porosity
  • Proto-Oncogene Proteins c-bcl-2 / metabolism


  • Culture Media, Conditioned
  • DNA, Mitochondrial
  • Oligomycins
  • Proto-Oncogene Proteins c-bcl-2
  • Adenosine Triphosphate
  • Electron Transport Complex I
  • Glucose
  • Galactose