Double-edged Sword Role of Iron-loaded Ferritin in Extracellular Vesicles.

The first life on earth was born under the ancient sea of abundant Fe(II) 3.8 Gya [ 1 , 2 ], and it is generally accepted that no independent life on earth can live without iron [ 3 ]. Iron is a major redox-active transition metal, which is used for various electron transfer reactions in the form of Fe(II), Fe-S cluster or heme [ 4 ]. During evolution, the life obtained the sulfhydryl systems [ 5 ], including glutathione, to counteract iron toxicity when present in excess, which might have been just insoluble FeS at first [ 6 , 7 ]. Finally, the life acquired the capacity to use molecular oxygen, which allows more flexible and versatile transfer of one to four electron(s) at a time and continuous electron flow inside the entire cells ( Fig. 1 ) [ 8 ].

Asbestos, a natural nanofibrous mineral, is still used worldwide, especially in some Asian countries, Russia, and South America due to the economic merits, in spite of the designation by World Health Organization as a definite human carcinogen (Group 1 by International Agency for Research on Cancer [IARC]) [ 45 ]. Asbestos is resistant to heat, acid and friction, and is also flexible for various industrial use. The association of asbestos exposure and mesothelioma is well established [ 45 , 46 ]. Asbestos is inhaled through the airway to the pulmonary parenchyma. However, the major target cells for carcinogenesis are parietal mesothelial cells in the pleural cavity, which has been a long mystery to be solved [ 47 , 48 ]. Molecular mechanisms underlying asbestos-induced mesothelioma have been intensively studies for these two decades. The important point is that the biopersistent nanofibers go through pulmonary parenchyma, by penetrating visceral pleura, into the pleural cavity after collecting hemoglobin originating from red blood cells on the surface and hence iron, depending on the negative pressure of the cavity, and then injures the parietal pleural mesothelial cells [ 48 , 49 ]. Amazingly, this process requires a few decades. The ability of mesothelial cells to phagocytose asbestos fibers provides a high risk for DNA double strand breaks and the resultant mutations because asbestos fibers present a high affinity for histones as well [ 50 , 51 ]. The tumor suppressor p16 INK4a is activated in response to DNA damage as well as oxidative stress. Therefore, it is no wonder that homozygous deletion of p16 INK4a is the major mutation observed in human and rat mesothelioma [ 52 , 53 ], representing direct DNA double-strand breaks by asbestos fiber in mesothelial cells and the following erroneous end-joining of DNA strands [ 47 , 48 ]. Of note, homozygous deletion of p16 INK4a is the major target mutation also in the Fenton reaction-induced renal cell carcinoma in rats [ 42 ]. However, the role of macrophages in mesothelial carcinogenesis has not been clear other than what is called “frustrated phagocytosis [ 54 ].” According to our 2020 report, macrophages generate mutagenic milieu for the surface mesothelial cells via ferroptosis, catalytic Fe(II)-dependent regulated necrosis accompanied by lipid peroxidation, upon taking up asbestos fibers as foreign material [ 55 ]. We have further sublimated this concept into a more concrete one in 2021 that macrophages under asbestos-induced ferroptosis emit ferroptosis-dependent extracellular vesicles (FedEVs) [ 56 ] which are received by mesothelial cells, resulting in significant mutagenic DNA lesions ( Fig. 4 ). Therefore, various cells, including macrophages, can share excess iron with the other cells of different types via ferritin in extracellular vesicles as safe non-catalytic Fe(III). However, a similar process, one involving FedEVs, may cause accumulation of excess iron in other specific cells, which may eventually contribute to carcinogenesis.

The major causes of human mortality in most countries are cancer and atherosclerosis (myocardial infarction and cerebral infarction/hemorrhage) except for emerging infectious diseases, such as COVID-19. We believe that these conditions, especially cancer, are associated with the long-term use of iron and oxygen [ 4 ]. Thus, modifying iron metabolism would be important as a practical way to prevent carcinogenesis. The present finding on the role of EVs in the transport of iron-loaded ferritin is important to consider future strategy for cancer prevention. We have been using plastics thus far so much in our daily life for convenience, which currently causes microplastics and nanoplastics pollution in the sea [ 57 ]. Surprisingly, the microplastics and nanoplastics are coming back to us as part of seafood diet [ 58 ], which is an emergent issue in current ecotoxicology to be further explored from the viewpoint of iron and foreign body.