The emerging role of iron dyshomeostasis in the mitochondrial decay of aging

Abstract

Recent studies show that cellular and mitochondrial iron increases with age. Iron overload, especially in mitochondria, increases the availability of redox-active iron, which may be a causal factor in the extensive age-related biomolecular oxidative damage observed in aged organisms. Such damage is thought to play a major role in the pathogenesis of iron overload diseases and age-related pathologies. Indeed, recent findings of the beneficial effects of iron manipulation in life extension in Caenorhabditis elegans, Drosophila and transgenic mice have sparked a renewed interest in the potential role of iron in longevity. A substantial research effort now focuses on developing and testing safe pharmacologic interventions to combat iron dyshomeostasis in aging, acute injuries and in iron overload disorders.

Scheme 1. Schematic illustration of mitochondrial iron dyshomeostasis with aging

Iron is transported into the mitochondrial matrix by iron importers (e.g. mitoferrin) where it can be directed to different pathways, including storage in frataxin, iron-sulfur cluster (ISC) biosynthesis, heme metabolism, mitochondrial ferritin (MtF) or other currently unknown pathways. The ISCs can be exported to the cytoplasma by ABCB7. Heme is thought to be exported from the mitochondrion by several pathways, including ABCG2, the feline leukemia virus subgroup-C receptor (FLVCR) and ABC-me. Defects in these transporters or defective biosynthesis of heme and ISCs with age impair mitochondrial iron homeostasis and lead to cellular degeneration. Increased labile iron with age, especially in mitochondria, has a strong potential to catalyze the generation of reactive oxygen species (ROS), resulting in cellular damage.