Over the past 15 years or so, numerous studies have sought to characterise how nuclear calcium (Ca²⁺) signals are generated and reversed, and to understand how events that occur in the nucleoplasm influence cellular Ca²⁺ activity, and vice versa. In this Commentary, we describe mechanisms of nuclear Ca²⁺ signalling and discuss what is known about the origin and physiological significance of nuclear Ca²⁺ transients. In particular, we focus on the idea that the nucleus has an autonomous Ca²⁺ signalling system that can generate its own Ca²⁺ transients that modulate processes such as gene transcription. We also discuss the role of nuclear pores and the nuclear envelope in controlling ion flux into the nucleoplasm.

The mitochondrial unfolded protein response (UPRmt) 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 UPRmt in the heart is unclear. The purpose of this study was to: 1) identify conditions that activate the UPRmt in the heart; and 2) study the relationship among the UPRmt, 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 UPRmt in cultured cardiomyocytes. The UPRmt was also induced in the hearts of mice subjected to chronic hemodynamic overload. Boosting the UPRmt 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 UPRmt 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 UPRmt in the mammalian (including human) heart exposed to pathological stresses. Enhancement of the UPRmt ameliorates mitochondrial and contractile dysfunction, suggesting that it may serve an important protective role in the stressed heart.

The transcription factor nuclear factor erythroid–derived 2-like 2 (Nrf2) controls a network of cytoprotective genes. Neither how Nrf2 is activated in the heart under hemodynamic overload nor its role and mechanism of action are known. This study aimed to investigate the activation and role of Nrf2 during chronic cardiac pressure overload. We first compared the responses of Nrf2 ^−/− mice and wild-type littermates to chronic pressure overload. Hearts of Nrf2 ^−/− mice showed impaired antioxidant gene expression, increased hypertrophy, and worse function compared with those of wild-type littermates after overload. Hearts of Nrf2 ^−/− mice had increased mitochondrial DNA damage, a caspase 8/BH3-interacting domain death agonist–related cleavage of mitochondrial apoptosis–inducing factor, nuclear DNA damage, and cell death. Nrf2 activation was under the control of the endogenous reactive oxygen species–generating enzyme nicotinamide adenine dinucleotide phosphate oxidase-4, both in vivo and in vitro. In mice with cardiac-specific overexpression of nicotinamide adenine dinucleotide phosphate oxidase-4, Nrf2 deletion significantly attenuated their protective phenotype during chronic pressure overload. This study identifies nicotinamide adenine dinucleotide phosphate oxidase-4–dependent upregulation of Nrf2 as an important endogenous protective pathway that limits mitochondrial damage and apoptosis-inducing factor–related cell death in the heart under hemodynamic overload.

Regular exercise has widespread health benefits. Fundamental to these beneficial effects is the ability of the heart to intermittently and substantially increase its performance without incurring damage, but the underlying homeostatic mechanisms are unclear. We identify the ROS-generating NADPH oxidase-4 (Nox4) as an essential regulator of exercise performance in mice. Myocardial Nox4 levels increase during acute exercise and trigger activation of the transcription factor Nrf2, with the induction of multiple endogenous antioxidants. Cardiomyocyte-specific Nox4-deficient (csNox4KO) mice display a loss of exercise-induced Nrf2 activation, cardiac oxidative stress and reduced exercise performance. Cardiomyocyte-specific Nrf2-deficient (csNrf2KO) mice exhibit similar compromised exercise capacity, with mitochondrial and cardiac dysfunction. Supplementation with an Nrf2 activator or a mitochondria-targeted antioxidant effectively restores cardiac performance and exercise capacity in csNox4KO and csNrf2KO mice respectively. The Nox4/Nrf2 axis therefore drives a hormetic response that is required for optimal cardiac mitochondrial and contractile function during physiological exercise.