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 journalArticle

11 Citations (Scopus)

Abstract

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
Volume1757
Issue number5-6
DOIs
StatePublished - May 1 2006

Fingerprint

Mitochondria
Mitochondrial DNA
Permeability
Cell death
Mutation
Cell Death
Mutagenesis
Peptides
Mitochondrial Membranes
Muscle Cells
Transgenic Mice
Apoptosis
Calcium
Membranes
Proteins

Keywords

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

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Cell Biology

Cite this

Mitochondrial DNA mutations cause resistance to opening of the permeability transition pore. / Mott, Justin L.; Zhang, Dekui; Chang, Shin Wen; Zassenhaus, H. Peter.

In: Biochimica et Biophysica Acta - Bioenergetics, Vol. 1757, No. 5-6, 01.05.2006, p. 596-603.

Research output: Contribution to journalArticle

Mott, Justin L. ; Zhang, Dekui ; Chang, Shin Wen ; Zassenhaus, H. Peter. / Mitochondrial DNA mutations cause resistance to opening of the permeability transition pore. In: Biochimica et Biophysica Acta - Bioenergetics. 2006 ; Vol. 1757, No. 5-6. pp. 596-603.
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