Super-suppression of mitochondrial reactive oxygen species signaling impairs compensatory autophagy in primary mitophagic cardiomyopathy

Moshi Song, Yun Chen, Guohua Gong, Elizabeth Murphy, Peter S. Rabinovitch, Gerald W. Dorn

Research output: Contribution to journalArticle

99 Scopus citations

Abstract

RATIONALE:: Mitochondrial reactive oxygen species (ROS) are implicated in aging, chronic degenerative neurological syndromes, and myopathies. On the basis of free radical hypothesis, dietary, pharmacological, and genetic ROS suppression has been tested to minimize tissue damage, with remarkable therapeutic efficacy. The effects of mitochondrial-specific ROS suppression in primary mitophagic dysfunction are unknown. OBJECTIVE:: An in vivo dose-ranging analysis of ROS suppression in an experimental cardiomyopathy provoked by defective mitochondrial clearance. METHODS AND RESULTS:: Mice lacking mitofusin 2 (Mfn2) in hearts have impaired parkin-mediated mitophagy leading to accumulation of damaged ROS-producing organelles and progressive heart failure. As expected, cardiomyocyte-directed expression of mitochondrial-targeted catalase at modest levels normalized mitochondrial ROS production and prevented mitochondrial depolarization, respiratory impairment, and structural degeneration in Mfn2 null hearts. In contrast, catalase expression at higher levels that supersuppressed mitochondrial ROS failed to improve either mitochondrial fitness or cardiomyopathy, revealing that ROS toxicity is not the primary mechanism for cardiac degeneration. Lack of benefit from supersuppressing ROS was associated with failure to invoke secondary autophagic pathways of mitochondrial quality control, revealing a role for ROS signaling in mitochondrial clearance. Mitochondrial permeability transition pore function was normal, and genetic inhibition of mitochondrial permeability transition pore function did not alter mitochondrial or cardiac degeneration, in Mfn2 null hearts. CONCLUSIONS:: Local mitochondrial ROS (1) contribute to mitochondrial degeneration and (2) activate mitochondrial quality control mechanisms. A therapeutic window for mitochondrial ROS suppression should minimize the former while retaining the latter, which we achieved by expressing lower levels of catalase.

Original languageEnglish (US)
Pages (from-to)348-353
Number of pages6
JournalCirculation research
Volume115
Issue number3
DOIs
StatePublished - Jul 18 2014

Keywords

  • cardiomyopathies
  • catalase
  • mitochondria
  • mitochondrial degradation
  • mitofusin 1

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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