Mitochondrial DNA mutations cause resistance to opening of the permeability transition pore

Justin L. Mott, Dekui Zhang, Shin Wen Chang, H. Peter Zassenhaus

Research output: Contribution to journalArticlepeer-review

11 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)596-603
Number of pages8
JournalBiochimica et Biophysica Acta - Bioenergetics
Issue number5-6
StatePublished - May 2006
Externally publishedYes


  • Apoptosis
  • Bcl-2
  • Calcium
  • Mitochondria
  • Permeability transition pore
  • mtDNA

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Cell Biology


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