Oxidative stress is not an obligate mediator of disease provoked by mitochondrial DNA mutations

Justin L. Mott, Dekui Zhang, Melissa Stevens, Shin Wen Chang, Grace Denniger, Hans Peter Zassenhaus

Research output: Contribution to journalArticle

41 Citations (Scopus)

Abstract

With age, mitochondrial DNA mutations and oxidative stress increase, leading to the hypothesis that the production of reactive oxygen species causes the pathogenic effects of mitochondrial DNA mutations. We tested this hypothesis using transgenic mice that develop cardiomyopathy due to the accumulation of mitochondrial DNA mutations specifically in the heart. Surprisingly, the mechanism of pathogenesis does not involve increased oxidative stress. The amounts of DNA and protein oxidative adducts are not elevated in the transgenic heart. Neither are signs of increased oxidative stress detected by measurements of enzyme function or oxidative defense systems. Rather, we find that the mitochondrial DNA mutations induce a cytoprotective response including increases in the levels of Bcl-2 and Bfl-1, pro-survival proteins that inhibit apoptosis, and atrial natriuretic factor. Bcl-2 is elevated in nearly all cardiomyocytes before the onset of dilated cardiomyopathy. These results raise the possibility that a signaling pathway between the mitochondrion and the nucleus mediates the pathogenic effect of mitochondrial DNA mutations.

Original languageEnglish (US)
Pages (from-to)35-45
Number of pages11
JournalMutation Research- Fundamental and Molecular Mechanisms of Mutagenesis
Volume474
Issue number1-2
DOIs
StatePublished - Mar 1 2001

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Mitochondrial DNA
Oxidative Stress
Mutation
Dilated Cardiomyopathy
Atrial Natriuretic Factor
Cardiomyopathies
Cardiac Myocytes
Transgenic Mice
Reactive Oxygen Species
Mitochondria
Proteins
Apoptosis
DNA
Enzymes

Keywords

  • Cardiomyopathy
  • Mitochondrial DNA mutations
  • Oxidative stress
  • Pathogenesis
  • mtDNA

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Health, Toxicology and Mutagenesis

Cite this

Oxidative stress is not an obligate mediator of disease provoked by mitochondrial DNA mutations. / Mott, Justin L.; Zhang, Dekui; Stevens, Melissa; Chang, Shin Wen; Denniger, Grace; Zassenhaus, Hans Peter.

In: Mutation Research- Fundamental and Molecular Mechanisms of Mutagenesis, Vol. 474, No. 1-2, 01.03.2001, p. 35-45.

Research output: Contribution to journalArticle

Mott, Justin L. ; Zhang, Dekui ; Stevens, Melissa ; Chang, Shin Wen ; Denniger, Grace ; Zassenhaus, Hans Peter. / Oxidative stress is not an obligate mediator of disease provoked by mitochondrial DNA mutations. In: Mutation Research- Fundamental and Molecular Mechanisms of Mutagenesis. 2001 ; Vol. 474, No. 1-2. pp. 35-45.
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