Mitochondrial DNA mutations cause resistance to opening of the permeability transition pore.
The age-related accumulation of mitochondrial DNA mutations has the potential to impair organ function and contribute to disease. In support of this hypothesis, accelerated mitochondrial mutagenesis is pathogenic in the mouse heart, and there is an increase in myocyte apoptosis. The current study sought to identify functional alterations in cell death signaling via mitochondria. Of particular interest is the mitochondrial permeability transition pore, opening of which can initiate cell death, while pore inhibition is protective. Here, we show that mitochondria from transgenic mice that develop mitochondrial DNA mutations have a marked inhibition of calcium-induced pore opening. Temporally, inhibited pore opening coincides with disease. Pore inhibition also correlates with an increase in Bcl-2 protein integrated into the mitochondrial membrane. We hypothesized that pore inhibition was mediated by mitochondrial Bcl-2. To test this hypothesis, we treated isolated mitochondria with Bcl-2 antagonistic peptides (derived from the BH3 domain of Bax or Bid). These peptides released the inhibition to pore opening. The data are consistent with a Bcl-2-mediated inhibition of pore opening. Thus, mitochondrial DNA mutations induce an adaptive-protective response in the heart that inhibits opening of the mitochondrial permeability pore.
Mott
Justin L
JL
Mayo Clinic College of Medicine, Guggenheim 17, Rochester, MN 55905, USA.
Zhang
Dekui
D
Chang
Shin-Wen
SW
Zassenhaus
H Peter
HP
D000595:Amino Acid Sequence; D000818:Animals; D051023:BH3 Interacting Domain Death Agonist Protein / Q000737:chemistry; D002118:Calcium / Q000502:physiology; D016923:Cell Death; D004272:DNA, Mitochondrial / Q000235:genetics*; D066298:In Vitro Techniques; D008564:Membrane Potentials; D051379:Mice; D008822:Mice, Transgenic; D008929:Mitochondria, Heart / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins / Q000502:physiology*; D051336:Mitochondrial Membranes / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D008969:Molecular Sequence Data; D009154:Mutation; D010446:Peptide Fragments / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction; D051028:bcl-2-Associated X Protein / Q000737:chemistry
D051023:BH3 Interacting Domain Death Agonist Protein; D004272:DNA, Mitochondrial; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D010446:Peptide Fragments; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D002118:Calcium