Mitochondrial reactive oxygen species and heme, non-heme iron metabolism

https://doi.org/10.1016/j.abb.2020.108695Get rights and content

Abstract

Mitochondria are one of the most important organelles for eukaryotes, including humans, to produce energy. In the energy-producing process, mitochondria constantly generate reactive oxygen species as a by-product of electrons leaking out from the electron transport chain react with oxygen. The active oxygen, in turn, plays pivotal roles in mediating several signalings, including those that are implicated in the development of some diseases such as neurodegenerative disease, cardiovascular disease, and carcinogenesis. This signaling, derived from mitochondrial reactive oxygen species, also affects intracellular iron homeostasis by regulating the expression of transporters. Heme iron is incorporated into cells through HCP1, and non-heme iron is transported by DMT1 in absorptive cells. Intracellular iron is exported by ferroportin and bound with transferrin. In most types of cell including erythrocyte, transferrin-bound iron is incorporated through transferrin-transferrin receptor system. We previously reported that the expression of HCP1 and DMT1 was upregulated in cancer cells and that overexpression of manganese superoxide dismutase, which is a mitochondrial-specific superoxide dismutase, downregulated the expression. These findings indicate that mitochondrial reactive oxygen species is associated with iron-related oxidative reactions. Recently, a mitochondria-specific iron transporter, mitoferrin, was identified, and the relationships among mitochondria, iron transportation, and diseases have been increasingly clarified.

Section snippets

The origin of mitochondria and reactive oxygen species from energy production

In the past 4.6 billion years of the history of the Earth, living organism have constantly evolved from bacteria as an ancestor. The highlight of the great evolution was the birth of mitochondria. Mitochondria arose approximately 1.5 billion years ago by transformation of ancestral bacteria into eukaryotes, followed by endosymbiotic transition [1]. The birth of mitochondria enabled aerobic metabolism, and the efficacy of energy production was dramatically improved. Aerobic metabolism is

Defense mechanism for oxidative stress and signaling via ROS

Mitochondria are the main producers of intracellular superoxide and also possess defense mechanisms to detoxify the reactivity (Fig. 1). Superoxide dismutase (SOD) is an enzyme that converts superoxide to oxygen and hydrogen peroxide [11]. SODs are of three types and have metal irons at the active center: Cu/ZnSOD (SOD1), MnSOD (SOD2), and extracellular SOD (ECSOD, SOD3) [11]. Cu/ZnSOD is located in the cytoplasm, MnSOD in mitochondria, and ECSOD outside the cells. Abnormality of these SODs

Mitochondrial ROS and cancer

ROS from mitochondria are associated with development of cancer, and elevated levels of ROS have been frequently detected in cancer cells [36]. Elevated levels of ROS in cancer activated the mitogen-activated protein kinase/extracellular-regulated kinase 1/2 (MAPK/Erk1/2) pathway and increased cellular proliferation [37,38]. We have clarified that invasion and migration of cancer cells are regulated by mitochondrial superoxide anion and that overexpression of MnSOD, which is localized

Mitochondrial ROS and iron metabolism

Iron is an essential nutrient for humans and is used for oxygen transport, DNA synthesis, and cell proliferation [43,44]. Once iron is incorporated into the body, it circulates in the blood combined with transferrin and is conserved in cells [45]. Intracellular nonfunctioning iron is detoxified and stored as ferritin [46]. Iron deficiency results in anemia, immune depression, psychiatric disorders, and so on [[47], [48], [49]]. In addition, iron reacts with other chemicals, and excess amounts

Conclusion

Mitochondria are one of the most important and essential organelles that generate energy for biological activity, and ROS, especially superoxide anion, produced as a by-product of mitochondrial aerobic metabolism play a wide range of roles, such as regulation of disease, apoptosis, and iron metabolism. For iron metabolism in particular, mitochondria play pivotal roles in both non-heme and heme incorporation and exportation. In recent years, a transporter of iron in mitochondria has been

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