A new study has shown that the mitochondrial Ca2+ uniporter (MCU) plays an essential role in iron overload-induced cardiac dysfunction and ferroptosis, which underlie cardiac myopathy in Friedreich ataxia (FA).
The study, published in Basic Research in Cardiology, found that inhibition of ferroptosis via MCU deficiency may be an effective approach to preventing cardiac dysfunction.
“It has recently been suggested that mitochondrial iron accumulation and probably ferroptosis mediate cardiac damage during ischemia-reperfusion (I/R) injury, making iron an important pathophysiological factor that warrants further study,” the authors wrote. “In the present study, we have used inducible conditional MCU knockout mice and determined the pivotal role of MCU and mitochondrial iron uptake in the occurrence of ferroptosis and cardiac dysfunction under iron loading conditions.”
The research team established iron overload in control (MCUfl/fl) and conditional MCU knockout (MCUf/f-MCM) mice by intraperitoneal iron dextran administration for 6 weeks, and then treated the mice with tamoxifen. They used Western blotting to determine MCU expression levels in heart tissue and cardiomyocytes.
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The results revealed that left ventricular function was reduced by chronic iron overload in the control mice but not in the MCU knockout mice. Isolated cardiomyocytes in the control mice developed ferroptosis after chronic iron treatment, but this did not occur in the MCU control mice.
Furthermore, in the control mice, Ca2+ transient amplitude and cell contractility were both significantly reduced after acute iron treatment, but this did not occur in the MCU knockout mice.
The authors conclude that, in iron-overload conditions in the heart, MCU plays an important role in causing mitochondrial dysfunction and ferroptosis and subsequent cardiac dysfunction. Cardiac-specific deficiency of MCU may represent an interesting treatment approach to preventing the cardiac myopathy that occurs in FA and other diseases associated with iron metabolism dysregulation.
Reference
Fefelova N, Wongjaikam S, Pamarthi, SH, et al. Deficiency of mitochondrial calcium uniporter abrogates iron overload-induced cardiac dysfunction by reducing ferroptosis. Basic Res Cardiol. Published online May 25, 2023. doi:10.1007/s00395-023-00990-7
