Abstract 546: Exploring MCUb Function in the Heart and Its Role in Ischemia Reperfusion Injury

Abstract

Mitochondrial calcium alterations can promote oxidative metabolism to match increasing functional demands during stress stimulation. However, mitochondrial calcium overload-induced cell death contributes to the pathogenesis of several cardiac disorders including ischemia reperfusion injury. The mitochondrial calcium uniporter (MCU) complex is the only identified transporter that permits rapid calcium uptake into mitochondria. While the biological function of the MCU pore-forming subunit has been annotated, much less is known about the MCUb protein, a high similarity paralog that is part of the greater MCU complex. The goal of our study was to investigate the biological function of MCUb, its role in mitochondrial calcium uptake, and its contribution to the pathogenesis of ischemia reperfusion injury in the heart. To address these questions, we generated both MCUb overexpressing mice as well as MCUb null mice. We observed that the cardiac-specific overexpression of MCUb inhibited mitochondrial calcium uptake, although basal mitochondrial calcium levels remained unchanged. Genetic ablation of MCUb, conversely, did not influence mitochondrial calcium uptake in the heart. MCUb null mice did not have differences in cardiac function by echocardiography, nor were tissue histological changes observed. This lack of an overt phenotype in MCUb null mice may be attributable to very low or even absent expression in the heart at baseline. However, induction of MCUb protein was observed in the hearts of mice subjected to ischemia reperfusion injury. Thus, mice were challenged with one-hour ischemia followed by 24-hour reperfusion and the ischemic area/area at risk was analyzed. Deletion of MCUb did not change the initial infarct size of the heart. However, MCUb null mice showed decreased fractional shortening 4-weeks after the ischemic injury. Gravimetric analysis as well as histological examination further supported the conclusion that MCUb deletion exacerbated damage in the heart after ischemia reperfusion injury. We are currently investigating the underlying mechanisms of this greater functional deficit.