Is the Therapeutic Window for Mitochondrial ROS Half-Open or Half-Closed?
Mixing Mitophagic Metaphors
The adult hearts relies on oxidative phosphorylation within the mitochondria as the primary source of energy production. A potential deleterious byproduct of oxidative phosphorylation 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 al6 now demonstrates that although attenuating ROS production to normal levels via expression of mitochondrial targeted catalase (mCAT) in a model of mitofusin (Mfn)-deficient cardiomyopathy promotes mitochondrial 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 mitochondrial 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 al6 extend their findings to suggest a therapeutic window of ROS suppression.
Article, see p 348
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 …