Reduction in mitochondrial iron alleviates cardiac damage during injury

Hsiang Chun Chang, Rongxue Wu, Meng Shang, Tatsuya Sato, Chunlei Chen, Jason S. Shapiro, Ting Liu, Anita Thakur, Konrad T. Sawicki, Sathyamangla Vn Prasad, Hossein Ardehali*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

38 Scopus citations

Abstract

Excess cellular iron increases reactive oxygen species (ROS) production and causes cellular damage. Mitochondria are the major site of iron metabolism and ROS production; however, few studies have investigated the role of mitochondrial iron in the development of cardiac disorders, such as ischemic heart disease or cardiomyopathy (CM). We observe increased mitochondrial iron in mice after ischemia/reperfusion (I/R) and in human hearts with ischemic CM, and hypothesize that decreasing mitochondrial iron protects against I/R damage and the development of CM. Reducing mitochondrial iron genetically through cardiac-specific overexpression of a mitochondrial iron export protein or pharmacologically using a mitochondria-permeable iron chelator protects mice against I/R injury. Furthermore, decreasing mitochondrial iron protects the murine hearts in a model of spontaneous CM with mitochondrial iron accumulation. Reduced mitochondrial ROS that is independent of alterations in the electron transport chain's ROS producing capacity contributes to the protective effects. Overall, our findings suggest that mitochondrial iron contributes to cardiac ischemic damage, and may be a novel therapeutic target against ischemic heart disease. Synopsis: Modulation of mitochondrial iron is shown to be a viable therapeutic approach against ischemic heart disease and heart failure, highlighting the need to develop more targeted iron chelators. Mitochondrial iron increases during and after I/R injury. Baseline mitochondrial iron contributes to ischemia/reperfusion injury. Decreasing mitochondrial iron at baseline is sufficient to protect against ischemia/reperfusion injury. Lower baseline mitochondrial iron is associated with decreased ROS production during cellular and tissue injury. Modulation of mitochondrial iron is shown to be a viable therapeutic approach against ischemic heart disease and heart failure, highlighting the need to develop more targeted iron chelators.

Original languageEnglish (US)
Pages (from-to)247-267
Number of pages21
JournalEMBO Molecular Medicine
Volume8
Issue number3
DOIs
StatePublished - Mar 1 2016

Keywords

  • Heart failure
  • Iron
  • Ischemia
  • Ischemia/reperfusion
  • Mitochondria

ASJC Scopus subject areas

  • Molecular Medicine

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