Ferroptosis: iron release mechanisms in the bioenergetic process

Abstract

Ferroptosis, an iron-dependent form of cell death, has been the focus of extensive research over the past decade, leading to the elucidation of key molecules and mechanisms involved in this process. While several studies have highlighted iron sources for the Fenton reaction, the predominant mechanism for iron release in ferroptosis has been identified as ferritinophagy, which occurs in response to iron starvation. However, much of the existing literature has concentrated on lipid peroxidation rather than on the mechanisms of iron release. This review proposes three distinct mechanisms of iron mobilization: ferritinophagy, reductive pathways with selective gating of ferritin pores, and quinone-mediated iron mobilization. Notably, the latter two mechanisms operate independently of iron starvation and rely primarily on reductants such as NADH and O₂•^-. The inhibition of the respiratory chain, particularly under the activation of α-ketoglutarate dehydrogenase, leads to the accumulation of these reductants, which in turn promotes iron release from ferritin and indirectly inhibits AMP-activated protein kinase through excessive iron levels. In this work, we delineate the intricate relationship between iron mobilization and bioenergetic processes under conditions of oxidative stress. Furthermore, this review aims to enhance the understanding of the connections between ferroptosis and these mechanisms.

Keywords: Ferritinophagy; Metabolic stress; Quinone-mediated iron mobilization; Reductive iron release; Selective gating.