Regulation of mitochondrial iron homeostasis in tumor cells

Iron is an indispensable trace element for all living organisms, existing in the form of free iron (Fe2+/Fe3+) and bound iron, and it plays a crucial role in a variety of cellular processes, including biomolecule synthesis, epigenetic regulation, immune modulation, cellular senescence, and mitochondrial respiration. Iron homeostasis is meticulously regulated within biological systems to avert the detrimental effects of both iron overload and deficiency, with imbalances leading to a multitude of diseases. Numerous studies have underscored the importance of rebalancing iron homeostasis in cancers, emphasizing its crucial role in tumorigenesis. Within the cell, mitochondria serve as the central hub for iron metabolism, primarily accountable for the synthesis of heme and iron-sulfur (Fe-S) clusters, the storage of excess iron via mitochondrial ferritin, and the regulation of iron-dependent cell death pathways such as ferroptosis and cuproptosis. Despite decades of in-depth research into the biological functions of iron and its homeostatic regulation, numerous scientific questions remain unresolved. This review offers a comprehensive and integrated analysis of the detailed regulatory mechanisms of mitochondrial iron metabolism and its profound influence on cancer metabolism. Based on the current research progress, we have summarized the challenges and limitations in this field and proposed new conceptual frameworks and research directions to enhance our understanding of mitochondrial iron biology in cancer.