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Circ Res. 2014 Jul 18;115(3):348-53. doi: 10.1161/CIRCRESAHA.115.304384. Epub 2014 May 29.

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

Author information

1
From the Department of Internal Medicine, Center for Pharmacogenomics, Washington University School of Medicine, St. Louis, MO (M.S., G.G., G.W.D.); National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (E.M.); and Department of Pathology, University of Washington, Seattle (P.S.R.).
2
From the Department of Internal Medicine, Center for Pharmacogenomics, Washington University School of Medicine, St. Louis, MO (M.S., G.G., G.W.D.); National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (E.M.); and Department of Pathology, University of Washington, Seattle (P.S.R.). gdorn@dom.wustl.edu.

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.

KEYWORDS:

cardiomyopathies; catalase; mitochondria; mitochondrial degradation; mitofusin 1

PMID:
24874428
PMCID:
PMC4106429
DOI:
10.1161/CIRCRESAHA.115.304384
[Indexed for MEDLINE]
Free PMC Article

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