We have sought to understand how mitochondrial calcium might regulate various physiological processes. To explore this area, we initially constructed a mouse model lacking MCU expression (Xin et al, Nature Cell Biol., 2013). These mice are viable and exhibit relatively little outward phenotypes except being slightly smaller than their wild type littermates. Cellular studies demonstrate that mitochondria from MCU-/- mice lack the ability to rapidly take up calcium arguing that MCU is indeed required for rapid calium uptake. There is a large literature suggesting that entry of calcium into the mitochondria triggers cell death. In this sense, it was surprising that we found no differences in the hearts of wild type and MCU-/- mice following exposure to ischemia-reperfusion injury (Xin et al., NCB, 2013). We are attemtping to understand the full implication of these observations in follow-up studies. We also have recently performed a more detailed characterization of the role of MCU in the heart (Holmstrom et al., JMCC, 2015). It is also becoming apparent that entry of calcium into the mitochondrial matrix is regulated by several proteins in addition to the pore subunit (MCU). These include proteins such as EMRE and MICU1 (see our review; Finkel et al., Circ Res, 2015). Genetic approaches to understand the function of these molecules is currently underway. In that regard, our first description of MICU1 deficient mice has been published(Liu et al., Cell Reports, 2016). Additional studies are underway to understand the in vivo function of EMRE. These studies include analyzing the role of the uniporter in ischemia reperfusion injury, metabolism and aging.
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