Early studies of mitochondria isolated from various tissues have demonstrated that Ca2+ uptake is driven by the membrane potential (??m), and is mediated by a ruthenium red-sensitive electrogenic uniport, referred to as ?Ca2+ uniporter? (mtCU). Electrophysiological recording of mtCU documented a similar inwardly rectifying Ca2+ current in mitoplasts derived from different tissues but great differences appeared in the current density, which was particularly low in cardiac mitochondria. Recently, the major mtCU forming proteins have been identified, including the pore, MCU, its dominant-negative form, MCUb, a scaffold, EMRE, and Ca2+-sensitive regulators, MICU1 and MICU2. To date, a MICU complex (a hetero/homo-dimer of MICU1 and MICU2) appears to determine both the threshold and cooperative activation of the mtCU by Ca2+, thus providing a mechanism for the sigmoidal [Ca2+] dependence of the mtCU. MICU1 deletion in mouse is perinatal lethal, likely because of mitochondrial Ca2+ overload-induced cell death. mtCU components show tissue-specific expression and MICU1 is expressed at a particularly low level in cardiac muscle. The tissue specific differences in the mtCU current and molecular composition of the mtCU -shown by our initial studies- are particularly interesting in the context of the distinct calcium signaling patterns that mitochondria from cardiac muscle and other tissues such as the liver have to cope with. Our preliminary results also show that heart failure patients have elevated cardiac MICU1 and MICU1-to-MCU ratio. We put forward the hypothesis that meeting the heart-specific calcium signaling needs depends on the relative abundance of the mtCU components, and adaptations to physiologic and pathogenic stress in the heart are associated with and determined by plasticity in the mtCU molecular composition. We also propose that the composition of the mtCU determines how mitochondrial Ca2+ uptake influences oxidative metabolism and mitochondrial fusion dynamics, which is central to keeping mitochondria in shape. The proposed studies will depend on an array of sophisticated live imaging techniques, novel genetic mouse models and animal models for heart failure. The hypothesis will be tested through the following specific aims.
Aim1 will determine the impact of the protein levels and stoichiometry of the mtCU components on the Ca2+-dependent regulation of mitochondrial Ca2+ uptake, ATP production and fusion dynamics in cardiac muscle.
Aim2 will determine the relevance of the mtCU protein profiles and the Ca2+ dependence of mitochondrial Ca2+ uptake on contractile function, including in the context of physiological and pathological stress. Collectively, these studies will be useful to establish how mtCU composition at the tissue level, namely the extent by which the population of MCUs is regulated by MICU1 and MICU2, and the resulting tissue-level pattern of mitochondrial Ca2+ uptake, determine the cardiac specific pattern of contractility, bioenergetics and mitochondrial quality control, under unchallenged conditions as well as under conditions of increased physiological or pathological cardiac workload.

Public Health Relevance

This proposal tests the hypothesis, that adaptations to exercise and pathogenic stress in the heart are associated with and determined by plasticity in the mtCU molecular composition. Experiments will use novel genetic mouse models to modify mitochondrial Ca2+ uniporter composition, cardiac stressors to model physiologically and pathologically elevated workload, the assessment of cardiac hypertrophy and (dys)function, and live imaging techniques to reveal the pathophysiological importance of Ca2+ uniporter composition and thus to point to possible new therapeutic targets.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Wong, Renee P
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Thomas Jefferson University
Schools of Medicine
United States
Zip Code
De La Fuente, Sergio; Lambert, Jonathan P; Nichtova, Zuzana et al. (2018) Spatial Separation of Mitochondrial Calcium Uptake and Extrusion for Energy-Efficient Mitochondrial Calcium Signaling in the Heart. Cell Rep 24:3099-3107.e4