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Abstract
Mitochondrial Ca2 + uptake influences energy production, cell survival, and Ca2 + signaling. The mitochondrial calcium uniporter, MCU, is the primary route for uptake of Ca2 + into the mitochondrial matrix. We have generated a zebrafish MCU mutant that survives to adulthood and exhibits dramatic cardiac phenotypes resembling cardiomyopathy and sinus arrest. MCU hearts contract weakly and have a smaller ventricle with a thin compact layer and reduced trabecular density. Damaged myofibrils and swollen mitochondria were present in the ventricles of MCU mutants, along with gene expression changes indicative of cell stress and altered cardiac structure and function. Using electrocardiography, we found that MCU hearts display conduction system defects and abnormal rhythm, with extended pauses resembling episodes of sinus arrest. Together, our findings suggest that proper mitochondrial Ca2 + homeostasis is crucial for maintaining a healthy adult heart, and establish the MCU mutant as a useful model for understanding the role of mitochondrial Ca2 + handling in adult cardiac biology.
Highlights
Calcium flux through the plasma membrane and intracellular organelles regulates cardiac contraction and energy metabolism
We examined whether MCULA2446 mutants manifest cardiac defects and found that the embryonic mitochondrial calcium uniporter (MCU) mutant hearts have normal morphology and function
Patches of disrupted α-actinin protein localization were present in MCU ventricular cardiomyocytes, suggesting the presence of disassembled sarcomeres (Figure 2F)
Summary
Calcium flux through the plasma membrane and intracellular organelles regulates cardiac contraction and energy metabolism. Ca2+ released from the sarcoplasmic reticulum initiates cardiac contraction and the entry of Ca2+ into the mitochondrial matrix activates critical enzymes of the TCA cycle and electron transport chain to promote ATP production. In addition to linking excitation-contraction coupling to energy metabolism, mitochondrial Ca2+ uptake shapes Ca2+ signals and regulates cell survival. Genetic manipulations in vitro and in vivo have established MCU’s critical roles in the heart. Given the important physiological roles of mitochondrial Ca2+ uptake in the heart, it is surprising that mice lacking MCU activity in cardiomyocytes have normal baseline cardiac function, TCA
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