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Iron: An Essential Element of Cancer Metabolism.

ABSTRACT: Cancer cells undergo considerable metabolic changes to foster uncontrolled proliferation in a hostile environment characterized by nutrient deprivation, poor vascularization and immune infiltration. While metabolic reprogramming has been recognized as a hallmark of cancer, the role of micronutrients in shaping these adaptations remains scarcely investigated. In particular, the broad electron-transferring abilities of iron make it a versatile cofactor that is involved in a myriad of biochemical reactions vital to cellular homeostasis, including cell respiration and DNA replication. In cancer patients, systemic iron metabolism is commonly altered. Moreover, cancer cells deploy diverse mechanisms to increase iron bioavailability to fuel tumor growth. Although iron itself can readily participate in redox reactions enabling vital processes, its reactivity also gives rise to reactive oxygen species (ROS). Hence, cancer cells further rely on antioxidant mechanisms to withstand such stress. The present review provides an overview of the common alterations of iron metabolism occurring in cancer and the mechanisms through which iron promotes tumor growth.

SUBMITTER: Hsu MY

PROVIDER: S-EPMC7761773 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Iron: An Essential Element of Cancer Metabolism.

Hsu Myriam Y MY Mina Erica E Roetto Antonella A Porporato Paolo E PE

Cells 20201203 12

Cancer cells undergo considerable metabolic changes to foster uncontrolled proliferation in a hostile environment characterized by nutrient deprivation, poor vascularization and immune infiltration. While metabolic reprogramming has been recognized as a hallmark of cancer, the role of micronutrients in shaping these adaptations remains scarcely investigated. In particular, the broad electron-transferring abilities of iron make it a versatile cofactor that is involved in a myriad of biochemical r ...[more]

PMID: 33287315

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Project description:BackgroundMammals and Drosophila melanogaster share some striking similarities in spermatogenesis. Mitochondria in spermatids undergo dramatic morphological changes and syncytial spermatids are stripped from their cytoplasm and then individually wrapped by single membranes in an individualization process. In mammalian and fruit fly testis, components of the mitochondrial iron metabolism are expressed, but so far their function during spermatogenesis is unknown. Here we investigate the role of Drosophila mitoferrin (dmfrn), which is a mitochondrial carrier protein with an established role in the mitochondrial iron metabolism, during spermatogenesis.ResultsWe found that P-element insertions into the 5'-untranslated region of the dmfrn gene cause recessive male sterility, which was rescued by a fluorescently tagged transgenic dmfrn genomic construct (dmfrnvenus). Testes of mutant homozygous dmfrnSH115 flies were either small with unorganized content or contained some partially elongated spermatids, or testes were of normal size but lacked mature sperm. Testis squashes indicated that spermatid elongation was defective and electron micrographs showed mitochondrial defects in elongated spermatids and indicated failed individualization. Using a LacZ reporter and the dmfrnvenus transgene, we found that dmfrn expression in testes was highest in spermatids, coinciding with the stages that showed defects in the mutants. Dmfrn-venus protein accumulated in mitochondrial derivatives of spermatids, where it remained until most of it was stripped off during individualization and disposed of in waste bags. Male sterility in flies with the hypomorph alleles dmfrnBG00456 and dmfrnEY01302 over the deletion Df(3R)ED6277 was increased by dietary iron chelation and suppressed by iron supplementation of the food, while male sterility of dmfrnSH115/Df(3R)ED6277 flies was not affected by food iron levels.ConclusionsIn this work, we show that mutations in the Drosophila mitoferrin gene result in male sterility caused by developmental defects. From the sensitivity of the hypomorph mutants to low food iron levels we conclude that mitochondrial iron is essential for spermatogenesis. This is the first time that a link between the mitochondrial iron metabolism and spermatogenesis has been shown. Furthermore, due to the similar expression patterns of some mitochondrial iron metabolism genes in Drosophila and mammals, it is likely that our results are applicable for mammals as well.

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Iron: An Essential Element of Cancer Metabolism.

Publications

Iron: An Essential Element of Cancer Metabolism.

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