Super-Suppression of Mitochondrial ROS Signaling Impairs Compensatory Autophagy in Primary Mitophagic Cardiomyopathy
Rationale: Mitochondrial reactive oxygen species (ROS) are implicated in aging, chronic degenerative neurological syndromes, and myopathies. Based on the 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 (Mfn) 2 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 (CAT) at modest levels normalized mitochondrial ROS production and prevented mitochondrial depolarization, respiratory impairment, and structural degeneration in Mfn2 null hearts. In contrast, CAT expression at higher levels that super-suppressed 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 super-suppressing 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 (MPTP) function was normal, and genetic inhibition of MPTP 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 CAT.
- Received May 15, 2014.
- Revision received May 28, 2014.
- Accepted May 29, 2014.