Mitochondrial iron accumulation with age and functional consequences

A.Y. Seo, J. Xu, S. Servais, T. Hofer, E. Marzetti, S.E. Wohlgemuth, M.D. Knutson, H.Y. Chung, and C. Leeuwenburgh
Institute on Aging, University of Florida, FL

Mitochondrial dysfunction, oxidative stress and apoptotic cell death are fundamental mechanisms that drive mammalian aging. Iron (Fe) mediated redox chemistry is particularly important because of its role in mitochondrial oxidative phosphorylation and other life-sustaining functions. Perturbation of mitochondrial Fe homeostasis causes a decline in mitochondrial function and plays a significant role in various neuromuscular degenerative diseases, as well as age-related tissue dysfunction. Hence, we investigated whether non-heme Fe accumulates in mitochondria with advancing age and furthermore, whether Fe overload causes mitochondrial oxidative damage and mitochondrial dysfunction. Specifically, our study investigated whether non-heme Fe levels increased over the course of aging in the quadriceps muscle interfibrillar mitochondria (IFM) and subsarcolemmal mitochondria (SSM) of Fischer 344 x Brown Norway rats. We also assessed mitochondrial susceptibility to apoptosis by measuring mitochondrial permeability transition pore (mPTP) openings and mitochondrial RNA oxidative damage. Furthermore, we investigated whether perturbation of mitochondrial Fe homeostasis differs between post-mitotic myofibers and mitotically active tissue, such as that found in the liver.

This study made several significant and novel findings. In particular, we determined for the first time that (i) non-heme Fe levels increase significantly with advancing age in mitochondria (IFM and SSM) of quadriceps muscle and liver tissue; (ii) levels of mitochondrial RNA oxidation increase during the aging process and correlate with mitochondrial levels of non-heme Fe; (iii) mitochondrial Fe is associated with an increased susceptibility of mPTP opening, possibly via the increased oxidative damage that occurs in mitochondria with age; and (iv) significant biochemical and physiological differences exist between skeletal muscle mitochondrial subpopulations (IFM and SSM), in terms of trace metal handling and functional parameters. Our study provides new insights into the role of mitochondrial Fe dyshomeostasis in cellular aging. Our findings also suggest that mitochondrial non-heme Fe represents a potential novel target for targeted interventions to slow aging. This research was supported by grants from the National Institute of Health to CL (AG17994 and AG21042) and a University of Florida Claude D. Pepper Older Americans Independence Center NIH grant (1 P30 AG028740).

Keywords: Mitochondrial iron homeostasis, Mitochondrial permeability transition pore, Mitochondrial RNA, Oxidative stress, Skeletal muscle subsarcolemmal and interfibrillar mitochondria