Modulating mitochondrial calcium in cardiac homeostasis and disease

Project Summary/Abstract A leading cause of death worldwide, heart failure is often linked to deficits in energy production in mitochondria. Mitochondrial uptake of cytosolic Ca2+ plays a critical role in matching energy production to demand by stimulating ATP production. However, mitochondrial Ca2+ in excess can lead to permeability transition pore opening and potentially cell death. Animal models of heart failure more closely akin to heart failure with reduced ejection fraction (HFrEF) are linked to increased mitochondrial Ca2+ in some studies and decreased mitochondrial Ca2+ in others; even less is known regarding the role of mitochondrial Ca2+ in heart failure with preserved ejection fraction (HFpEF). With the long-term goal of helping to develop therapies to limit or restore mitochondrial Ca2+ when appropriate to improve clinical outcomes in HFrEF and HFpEF, this application will map out the contribution of increased and decreased mitochondrial Ca2+ to cardiac dysfunction in homeostasis and in mouse models of pressure overload and high fat/high sucrose diet with L-NAME. Tamoxifen-inducible cardiac-specific deletion of Micu1, the gene encoding the “gatekeeper” of mitochondrial Ca2+ uniporter complex (mtCU), will be used to induce mitochondrial Ca2+ overload. In the same manner, deletion of Emre, the gene encoding the essential regulator of the mtCU, will be used to eliminate mtCU activity and lower mitochondrial Ca2+. The overall objective in this application is to systematically compare the effects of increased and decreased mitochondrial Ca2+ on measures of cardiac health – mitochondrial function, tissue histology, contractility before and after stimulation – in homeostasis and in two different types of induced heart failure. The central hypothesis is that elevated mtCa2+ impairs heart function in homeostasis and in HFrEF, whereas lowered mtCa2+ has negative effects in energetically demanding states and in HFpEF. The rationale is that based on the literature and our preliminary data, pressure overload forces the heart to work harder, elevating mitochondrial Ca2+, while some indications suggest that mice fed the high fat/high sucrose diet with L-NAME have lower mitochondrial Ca2+. Hence, in the former conditions, increased mitochondrial Ca2+ is detrimental, and in the latter, decreased mitochondrial Ca2+ is detrimental. The central hypothesis will be tested by pursuing two specific aims: 1) Assess how elevated and reduced mitochondrial Ca2+ impact cardiac homeostasis; and 2) Assess how elevated and reduced mitochondrial Ca2+ impact HFrEF and HFpEF- MetS. This research is conceptually innovative in using genetic manipulation to modulate mitochondrial Ca2+, and in directly comparing elevated and reduced mitochondrial Ca2+ in models approximating HFrEF and HFpEF. The outcomes of this research are expected to be significant by establishing a new paradigm regarding mitochondrial Ca2+ in HFrEF and HFpEF, with the potential to inform future therapeutic strategies.