The diversified role of mitochondria in ferroptosis in cancer

Abstract

Ferroptosis is a form of regulated cell death induced by iron-dependent lipid peroxidation, and it has been studied extensively since its discovery in 2012. Induced by iron overload and ROS accumulation, ferroptosis is modulated by various cellular metabolic and signaling pathways. The GSH-GPX4 pathway, the FSP1-CoQ10 pathway, the GCH1-BH4 pathway, the DHODH-CoQH2 system and the sex hormones suppress ferroptosis. Mitochondrial iron metabolism regulates ferroptosis and mitochondria also undergo a morphological change during ferroptosis, these changes include increased membrane density and reduced mitochondrial cristae. Moreover, mitochondrial energy metabolism changes during ferroptosis, the increased oxidative phosphorylation and ATP production rates lead to a decrease in the glycolysis rate. In addition, excessive oxidative stress induces irreversible damage to mitochondria, diminishing organelle integrity. ROS production, mitochondrial membrane potential, mitochondrial fusion and fission, and mitophagy also function in ferroptosis. Notably, some ferroptosis inhibitors target mitochondria. Ferroptosis is a major mechanism for cell death associated with the progression of cancer. Metastasis-prone or metastatic cancer cells are more susceptible to ferroptosis. Inducing ferroptosis in tumor cells shows very promising potential for treating drug-resistant cancers. In this review, we present a brief retrospect of the discovery and the characteristics of ferroptosis, then we discuss the regulation of ferroptosis and highlight the unique role played by mitochondria in the ferroptosis of cancer cells. Furthermore, we explain how ferroptosis functions as a double-edged sword as well as novel therapies aimed at selectively manipulating cell death for cancer eradication.

Fig. 1. The major signaling pathways in ferroptosis.

The GPX4-GSH pathway occurs mainly in the cytoplasm (cGPX4) and mitochondria (mGPX4). This axis can be inhibited by FINs and tumor suppressor p53. The FSP1-CoQ pathway occurs in the plasma membrane which can be inhibited by iFSP. The GCH1-BH4 pathway starts from the substrate GTP and inhibits lipid peroxidation by BH4–BH2 cycle. The DHODH-CoQH2 pathway is located at the outer surface of inner mitochondrial membrane, which catalyzes the conversion of DHO to OA while simultaneously refreshing CoQH2 to clear lipid radicals. SLC7A11 solute carrier family 7 member 11, cGPX4 cytoplasmic glutathione peroxidase 4, GSH glutathione, GSSG glutathione disulfide, PL-OO· Phospholipid hydroperoxide, FIN ferroptosis inducing, PULA long-chain polyunsaturated fatty acids, ACSL4: acyl-CoA synthetase long-chain family member 4, FSP1: ferroptosis suppressor protein 1; iFSP1 FSP1 small-molecule inhibitor, GCH1 cyclohydrolase-1, GTP cyclohydrolase-1, PTS 6-pyruvoyltetrahydropterin synthase, SPR sepiapterin reductase, DHFR dihydrofolate reductase, DHODH dihydroorotate dehydrogenase, OA orotate, DHO dihydroorotate, mGPX4 mitochondrial glutathione peroxidase 4.

Fig. 2. The iron metabolism in mitochondria.

Fe³⁺ enters cytosol via the transporter TfR1, with the help of endosome and other transporters, the Fe²⁺ generated, Fe²⁺ enters into mitochondria mainly via three passways: (1) by VDAC 2/3 and Mfrn1/Mfrn2 (2) by the mPTP (3) by the Ca²⁺ uniporter. The mitochondrial iron metabolism mainly occurs in the mitochondria matrix. The iron in mitochondria is utilized for the synthesis of cofactors including heme and iron-sulfur (Fe/S) clusters essential to the function of enzymes involved in oxidation-reduction reactions. Mitochondria contain a labile iron pool and the balance of iron homeostasis is controlled by FtMt. The dysfunction of mitoNEET or unbalance of iron metabolism lead to the accumulation of iron in mitochondria, the increase of ROS, MMP and mitochondria swelling and the energy production change.

Fig. 3. Mitochondria OXPHOS pathway and TCA cycle participate in the ferroptosis.

AMPK is the energy sensor, cancer cells with high basal AMPK activation are resistant to ferroptosis and AMPK inactivation sensitizes these cells to ferroptosis. Mechanistically, AMPK regulates ferroptosis through acetyl-CoA carboxylase (ACC) and polyunsaturated fatty acid (PUFA) biosynthesis. TCA metabolites such as α-KG and its downstream products succinic acid and fumaric acid could all enhance the ferroptosis induced by cysteine depletion.

Fig. 4. Crosstalk between mitochondria and ferroptosis.

The mitochondria iron metabolism and ROS production affect ferroptosis, the overloading of iron and the excessive ROS induces ferroptosis. In the process of ferroptosis, the mitochondria morphology changes. Critical enzymes working in mitochondria such as DHODH and CoQ10 inhibit ferroptosis.