Cardioprotective Effect of the Mitochondrial Unfolded Protein Response During Chronic Pressure Overload

The mitochondrial unfolded protein response (UPR^mt) is activated when misfolded proteins accumulate within mitochondria and leads to increased expression of mitochondrial chaperones and proteases to maintain protein quality and mitochondrial function. Cardiac mitochondria are essential for contractile function and regulation of cell viability, while mitochondrial dysfunction characterizes heart failure. The role of the UPR^mt in the heart is unclear.

The purpose of this study was to: 1) identify conditions that activate the UPR^mt in the heart; and 2) study the relationship among the UPR^mt, mitochondrial function, and cardiac contractile function.

Cultured cardiac myocytes were subjected to different stresses in vitro. Mice were subjected to chronic pressure overload. Tissues and blood biomarkers were studied in patients with aortic stenosis.

Diverse neurohumoral or mitochondrial stresses transiently induced the UPR^mt in cultured cardiomyocytes. The UPR^mt was also induced in the hearts of mice subjected to chronic hemodynamic overload. Boosting the UPR^mt with nicotinamide riboside (which augments NAD⁺ pools) in cardiomyocytes in vitro or hearts in vivo significantly mitigated the reductions in mitochondrial oxygen consumption induced by these stresses. In mice subjected to pressure overload, nicotinamide riboside reduced cardiomyocyte death and contractile dysfunction. Myocardial tissue from patients with aortic stenosis also showed evidence of UPR^mt activation, which correlated with reduced tissue cardiomyocyte death and fibrosis and lower plasma levels of biomarkers of cardiac damage (high-sensitivity troponin T) and dysfunction (N-terminal pro-B-type natriuretic peptide).

These results identify the induction of the UPR^mt in the mammalian (including human) heart exposed to pathological stresses. Enhancement of the UPR^mt ameliorates mitochondrial and contractile dysfunction, suggesting that it may serve an important protective role in the stressed heart.