Abstract 17534: mitoNEET Regulates Mitochondrial Iron Homeostasis Interacting With Transferrin Receptor

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Abstract

Introduction: Iron is an essential trace element for regulation of redox and mitochondrial function, and then mitochondrial iron content is tightly regulated in mammals. We focused on a novel protein localized at the outer mitochondrial membrane, mitoNEET, for mitoNEET contained iron/sulfur clusters and has been associated with mitochondrial respiration. However, the role of mitoNEET in mitochondrial iron homeostasis has not been elucidated.

Methods and Results: Firstly, there was a significant positive correlation between mitoNEET expression levels and mitochondrial respiration. Secondary, mass spectrometry analysis revealed that mitoNEET interacted with transferrin receptor in vitro. Moreover mitoNEET was endogenously coprecipitated with transferrin receptor in the heart, which indicates that mitoNEET also interacts with transferrin receptor in vivo. Next, we generated mice with cardiac-specific deletion of mitoNEET (mitoNEET-knockout). mitoNEET flox/flox mice, which was used as control mice, was generated with lox-P and homologous recombination strategies. Cardiac-specific deletion was achieved using αMHC-Cre. Transferrin receptor expression levels in the mitochondria from mitoNEET-knockout mice was lower than from the control mice, suggesting that mitoNEET interact with transferrin receptor on the outer mitochondrial membrane in vivo. Iron contents in isolated mitochondria were significantly increased in mitoNEET-knockout mice compared to control mice. Mitochondrial reactive oxygen species (ROS) were higher in mitoNEET-knockout mice compared to control mice. Mitochondrial state 3 respirations were comparable between the groups, but mitochondrial maximal capacity and reserve capacity were significantly decreased in 12-month-old mitoNEET-knockout mice compared to control mice. Cardiac dysfunction, evaluated by echocardiography, was also observed in 12-month-old mitoNEET-knockout mice.

Conclusions: The complex formation of mitoNEET with transferrin receptor may regulate mitochondrial iron contents via an influx of iron. A disruption of mitoNEET could thus be involved in mitochondrial ROS production by iron overload in the heart.

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