Mitochondrial Unfolded Protein Response (UPR^mt) Activation in Cardiac Diseases

As reported by Smyrnias et al. (1), pre-induction of mitochondrial unfolded protein response (UPR^mt) using nicotinamide riboside is sufficient to prevent cardiac dysfunction induced by chronic hemodynamic overload in rodents. These findings open up a new avenue for strategies targeting mitochondrial dysfunction to treat cardiovascular diseases (2) and raise important questions that should be addressed to pursue the UPR^mt activation as a feasible therapy.

First, the magnitude of UPR^mt activation observed by Smyrnias et al. (1) varies between a 0.3- and 10-fold increase among conditions (cell culture, mouse, and human data) in which UPR^mt activation seems to have no clear association with a phenotype (beneficial or detrimental). For example, chronic hemodynamic overload increases cardiac levels of UPR^mt markers ~50% (VS. a 30% increase in healthy nicotinamide riboside–treated animals) compared with control subjects. However, pre-induction of UPR^mt using nicotinamide riboside has a remarkable positive effect on mitochondrial and cardiac function upon hemodynamic stress. Considering the key role of nicotinamide adenine dinucleotide in cardiac physiology (3), the UPR^mt-dependent effect of nicotinamide riboside must still be determined.

Second, drugs used to treat cardiac diseases work mainly thorough inhibition of neurohumoral hyperactivation (i.e., angiotensin-receptor blockers, angiotensin-converting enzyme inhibitors, AT₁ antagonists), thereby minimizing the cardiac stress. Here, there is an intriguing and somewhat counter-intuitive situation in which both disease (or conditions mimicking the disease in culture) and treatment (measured according to messenger ribonucleic acid levels) improve the UPR^mt signal. Consequently, it becomes critical to dissect the extension and overlap of cardiac UPR^mt activation upon different interventions, thus contributing to a better understanding of its compensatory, deleterious, or neutral (associative) effects. This approach will be helpful to screen and develop drugs targeting cardiac UPR^mt. Other questions related to the effectiveness and toxicity of pharmacological cardiac UPR^mt activation (including transient vs. sustained activation or prevention vs. therapy), as well as its dependence on mitochondrial dysfunction, also need to be addressed to define the best clinical need for such intervention. Finally, there will be a translational challenge finding molecules capable of boosting UPR^mt in failing human hearts, in which the UPR^mt is already hyperactivated.