Although iron is a trace metal that is essential for several life-sustaining functions, it can also serve as a potent pro-oxidant and catalyst for the formation of reactive oxygen species in biological systems [1-3]. We have recently found that the iron content was elevated with age in rat heart (preliminary data) and quadriceps mitochondria [4-6]. Mitochondria are important generators of energy, providing ATP through oxidative phosphorylation. They also play a key role in cell death, as reported for various cardiac pathologies, including ischemia/reperfusion injury, cardiomyopathy, and congestive heart failure [7-9]. However, it is not known whether and how perturbations in iron homeostasis, specifically within mitochondria, contribute to mitochondria-mediated oxidative stress and cell death in the aging heart. The objective of this study is to identify the role of iron in mitochondrial function and oxidative stress in the aging heart in vitro and in vivo and to test interventions aimed at attenuating the decline in mitochondrial function observed with age. Thus, our long term goal is to explore the role of iron homeostasis in aging hearts, as well as potential interventions for preventive therapeutic purposes. Our central hypothesis is that cellular and mitochondrial iron content increases with age in heart mitochondria due to impaired iron homeostatic regulation, which sensitizes hearts to mitochondrial permeability transition onset, oxidative damage and impairs bioenergetics. In addition, we hypothesize that iron overload plays a causal role in mitochondrial oxidant production and dysfunction, which should be attenuated by chelation therapy.
