A proper balance of metabolism in the heart is fundamental to guarantee an adequate energetic production and prevents alterations, like excessive ROS generation and mitochondrial misfunctions. Indeed, when the heart is subjected to stress, from very early time points it rewires its energetic metabolism and undergoes an increased ROS production, suggesting a crucial role for these two parameters in the pathologic cardiac response. In previous works, we described the protective role of the chaperone protein melusin in the heart under stress, demonstrating that melusin over-expression sustains the myocardial hypertrophic response, conversely its absence causes a rapid transition toward myocardial dilation and failure. In our lab, we investigated the role of melusin in modulating myocardial metabolism and its response to stressful stimuli.
We recently found that melusin is able to modulate cardiac fatty acid oxidation (FAO), by inhibiting the mitochondrial trifunctional protein (MTP), and this reduces, in turn, ROS generation in the heart. Indeed, in absence of melusin, the heart has a higher rate of palmitate oxidation in physiologic conditions that causes a higher generation of ROS. When melusin null hearts are subjected to a stressful stimulus, as doxorubicin toxicity or pressure overload induced by aortic banding, they experience a fall down in FAO and a broad increase in ROS generation. These alterations, in turn, compromise the mitochondrial function and the energetic production. The treatment with a lipid metabolism modulator, acting similarly to melusin on MTP, reverse the alterations occurring in melusin null hearts in physiologic and stress conditions. We described a new mechanism of metabolic regulation in the heart mediated by the chaperone protein melusin. Melusin, by reducing FAO and ROS generation in physiologic state, ameliorates the cardiac response to stressful stimuli.