Deficiency of mitochondrial calcium uniporter abrogates iron overload-induced cardiac dysfunction by reducing ferroptosis.

Abstract

Iron overload associated cardiac dysfunction remains a significant clinical challenge whose underlying mechanism(s) have yet to be defined. We aim to evaluate the involvement of the mitochondrial Ca²⁺ uniporter (MCU) in cardiac dysfunction and determine its role in the occurrence of ferroptosis. Iron overload was established in control (MCU^fl/fl) and conditional MCU knockout (MCU^fl/fl-MCM) mice. LV function was reduced by chronic iron loading in MCU^fl/fl mice, but not in MCU^fl/fl-MCM mice. The level of mitochondrial iron and reactive oxygen species were increased and mitochondrial membrane potential and spare respiratory capacity (SRC) were reduced in MCU^fl/fl cardiomyocytes, but not in MCU^fl/fl-MCM cardiomyocytes. After iron loading, lipid oxidation levels were increased in MCU^fl/fl_, but not in MCU^fl/fl-MCM hearts. Ferrostatin-1, a selective ferroptosis inhibitor, reduced lipid peroxidation and maintained LV function in vivo after chronic iron treatment in MCU^fl/fl hearts. Isolated cardiomyocytes from MCU^fl/fl mice demonstrated ferroptosis after acute iron treatment. Moreover, Ca²⁺ transient amplitude and cell contractility were both significantly reduced in isolated cardiomyocytes from chronically Fe treated MCU^fl/fl hearts. However, ferroptosis was not induced in cardiomyocytes from MCU^fl/fl-MCM hearts nor was there a reduction in Ca²⁺ transient amplitude or cardiomyocyte contractility. We conclude that mitochondrial iron uptake is dependent on MCU, which plays an essential role in causing mitochondrial dysfunction and ferroptosis under iron overload conditions in the heart. Cardiac-specific deficiency of MCU prevents the development of ferroptosis and iron overload-induced cardiac dysfunction.