Mitochondrial regulation of ferroptosis

Abstract

Ferroptosis is a form of iron-dependent regulated cell death driven by uncontrolled lipid peroxidation. Mitochondria are double-membrane organelles that have essential roles in energy production, cellular metabolism, and cell death regulation. However, their role in ferroptosis has been unclear and somewhat controversial. In this Perspective, I summarize the diverse metabolic processes in mitochondria that actively drive ferroptosis, discuss recently discovered mitochondria-localized defense systems that detoxify mitochondrial lipid peroxides and protect against ferroptosis, present new evidence for the roles of mitochondria in regulating ferroptosis, and outline outstanding questions on this fascinating topic for future investigations. An in-depth understanding of mitochondria functions in ferroptosis will have important implications for both fundamental cell biology and disease treatment.

Figure 1.

The ferroptosis pathway. ACSL4 and LPCAT3 mediate the biosynthesis of PUFA-containing PLs, which are susceptible to peroxidation through both nonenzymatic and enzymatic mechanisms. Excessive accumulation of lipid peroxides on cellular membranes can result in ferroptosis. Cells have evolved at least four defense systems with different subcellular localization to keep lipid peroxides in check and thereby protect cells against ferroptosis, including (1) cytosolic and mitochondrial GPX4, (2) FSP1 on plasma membrane, (3) DHODH in mitochondria, and (4) GCH1 (whose exact subcellular localization remains unclear). BH4, tetrahydrobiopterin; cyto, cytosolic; DHO, dihydroorotate; mito, mitochondrial; OA, orotate.

Figure 2.

The role of mitochondria in promoting ferroptosis. Energy stress–mediated AMPK activation blocks ferroptosis by suppressing ACC-mediated conversion of acetyl-CoA to malonyl-CoA, a precursor for PUFA synthesis. ETCs in mitochondria drive proton motive force and ATP synthesis, which counteracts energy stress–induced AMPK activation and thereby promotes ferroptosis. In addition, the electron leakage from ETC complexes I and III produces O₂^•−, which can promote PUFA peroxidation and thereby ferroptosis. Glutaminolysis and the TCA cycle in mitochondria can drive ETC activities and further promote ferroptosis. C, cytochrome c; O₂^•−, superoxide; ^•OH, hydroxyl radicals; Q, ubiquinol.

Figure 3.

GPX4^mito/DHODH and GPX4^cyto/FSP1 constitute two separate defense systems to detoxify lipid peroxides and suppress ferroptosis in cells.(A) GPX4^mito and DHODH suppress lipid peroxidation in mitochondria, whereas GPX4^cyto and FSP1 detoxify lipid peroxides in nonmitochondrial compartments, including the plasma membrane. In each compartment, GPX4 has a more important role in neutralizing lipid peroxides than DHODH or FSP1. (GCH1 is not shown here because its subcellular localization currently remains elusive.) (B–D) Depending on RSL3 doses and DHODH status, RSL3 treatment can induce potent lipid peroxidation in nonmitochondrial compartments, mitochondria, or both compartments, resulting in ferroptosis. Note that RSL3 treatment significantly increases DHODH activity (B). cyto, cytosolic; mito, mitochondrial.