Is the therapeutic window for mitochondrial ROS half-open or half-closed? Mixing mitophagic metaphors.

T he adult hearts relies on oxidative phosphorylation within the mitochondria as the primary source of energy production. A potential deleterious byproduct of oxidative phosphor-ylation is the generation of reactive oxygen species (ROS), 1 and thus cardiac mitochondria are currently appreciated as the major source of ROS within the heart. Subsequently, elevations in mitochondrial ROS production have been identified as a key mediatory of many of the pathological changes that occur in the failing heart. 1–4 Yet, therapeutic strategies to reduce ROS have failed to yield outcomes that might have been expected based on the supporting data, 5 and it is important that we continue to expand out understanding of ROS signaling in the heart in order that we might improve treatment outcomes. Recent work by Song et al 6 now demonstrates that although attenuating ROS production to normal levels via expression of mitochondrial targeted catalase (mCAT) in a model of mi-tofusin (Mfn)-deficient cardiomyopathy promotes mitochon-drial fitness, the super suppression of ROS with high mCAT fails to improve mitochondrial quality. High mCAT levels in this Mfn deletion model were instead related to impairment of secondary autophagic pathways associated with mitochon-drial quality control. The implication of this finding is that the contribution of local mitochondrial ROS to mitochondrial degradation is an important component of mitophagy-dependent quality control. Song et al 6 extend their findings to suggest a therapeutic window of ROS suppression. ROS production increases in damaged mitochondria, and therefore, it is important that quality control mechanisms are in place to cull damaged mitochondria. 7 Mitophagy is a specialized form of autophagy that maintains mitochondrial quality control in the heart. A principal component of mitochondrial culling through mitophagy is Mfn2. 8 Mfn2, along with Mfn1, are outer mitochondrial membrane fusion proteins that serve multiple functions. Mfn1 and 2 tether mitochondria to the sarcoplasmic reticulum, facilitating close communication between the sarcoplasmic reticulum and the mitochondria 9 ; permit outer mitochondrial remodeling during mitochondrial fusion 10 ; and facilitate parkin-mediated mitophagy. 8 Phosphorylation of Mfn2 by the PTEN (phosphatase and tensin homolog)-inducible kinase 1 leads to parkin recruitment to damaged mitochondria and initiates mitophagic removal. 8 Loss of Mfn2 expression in the heart leads to the accumulation of abnormal mitochondria and a delayed car-diomyopathy. 8 In this issue of Circulation Research, Song et al 6 have addressed the contribution of ROS to the delayed car-diomyopathy in the Mfn2 null mouse. ROS levels are …