Iron accumulation in senescent cells is coupled with impaired mitochondrial homeostasis and inhibition of ferroptosis

Cellular senescence is characterized by proliferation inhibition and functional decline, which leads to cell damage and death. It is an irreversible process and a pathogenic factor in many age-related diseases. Aging is a complex biological process that is often accompanied by the occurrence of various forms of programmed cell death，such as ferroptosis. We found that senescent cells alter iron metabolism, including transport, storage, and utilization. In senescent cells induced by radiation, hydrogen peroxide, or passaging, large amounts of iron accumulate, accompanied by changes in the levels of iron homeostasis-related proteins. For example, the high expression of ferritin and transferrin in the cytoplasm and mitochondria drives cellular iron accumulation, senescence, and resistance to ferroptosis. The resistance of senescent cells to ferroptosis mainly depends on the transport and storage of iron by ferritin and transferrin. During cellular senescence, knockdown of mitochondrial transferrin sensitizes cells to ferroptosis, while knockdown of ferritin does not, indicating that mitochondrial utilization of iron help senescent cells resist ferroptosis. The accumulation of dysfunctional mitochondria drives cellular senescence. Iron, as a cofactor for many mitochondrial proteins, plays a key role in cellular respiration and energy metabolism. In senescent cells, we observed an increase in the synthesis of heme and iron-sulfur clusters, which provides the necessary precursors for the formation of dysfunctional mitochondria. Finally, in the lung tissues of aged mice, iron accumulation was found to be accompanied by the upregulation of genes related to iron transport and storage, as well as heme and iron-sulfur cluster synthesis. By subcutaneously injecting MSCs into mice, we validated in the in vivo environment that knockdown of mitochondrial transferrin sensitized senescent cells to ferroptosis. Therefore, this study investigates the role of iron metabolism in maintaining cellular senescence and counteracting ferroptosis, thereby providing new targets for the elimination of senescent cells and the treatment of age-related diseases.