Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field.

https://biblio.ugent.be/publication/8555786/file/8555788.pdf

Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018.

The N-terminal domains of gasdermin proteins cause pyroptotic cell death by oligomerizing to form membrane pores.

Pore-forming activity and structural autoinhibition of the gasdermin family

Ferroptosis is a form of regulated cell death that is caused by the iron-dependent peroxidation of lipids1,2. The glutathione-dependent lipid hydroperoxidase glutathione peroxidase 4 (GPX4) prevents ferroptosis by converting lipid hydroperoxides into non-toxic lipid alcohols3,4. Ferroptosis has previously been implicated in the cell death that underlies several degenerative conditions2, and induction of ferroptosis by the inhibition of GPX4 has emerged as a therapeutic strategy to trigger cancer cell death5. However, sensitivity to GPX4 inhibitors varies greatly across cancer cell lines6, which suggests that additional factors govern resistance to ferroptosis. Here, using a synthetic lethal CRISPR–Cas9 screen, we identify ferroptosis suppressor protein 1 (FSP1) (previously known as apoptosis-inducing factor mitochondrial 2 (AIFM2)) as a potent ferroptosis-resistance factor. Our data indicate that myristoylation recruits FSP1 to the plasma membrane where it functions as an oxidoreductase that reduces coenzyme Q10 (CoQ) (also known as ubiquinone-10), which acts as a lipophilic radical-trapping antioxidant that halts the propagation of lipid peroxides. We further find that FSP1 expression positively correlates with ferroptosis resistance across hundreds of cancer cell lines, and that FSP1 mediates resistance to ferroptosis in lung cancer cells in culture and in mouse tumour xenografts. Thus, our data identify FSP1 as a key component of a non-mitochondrial CoQ antioxidant system that acts in parallel to the canonical glutathione-based GPX4 pathway. These findings define a ferroptosis suppression pathway and indicate that pharmacological inhibition of FSP1 may provide an effective strategy to sensitize cancer cells to ferroptosis-inducing chemotherapeutic agents. A synthetic lethal CRISPR–Cas9 screen identifies ferroptosis suppressor protein 1 as a key ferroptosis-resistance factor, the expression of which correlates with ferroptosis resistance in hundreds of cancer cell lines.

/pdf/the-coq-oxidoreductase-fsp1-acts-parallel-to-gpx4-to-inhibit-3stdxgzjbs.pdf

The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis.

Ferroptosis is an iron-dependent form of necrotic cell death marked by oxidative damage to phospholipids1,2. To date, ferroptosis has been thought to be controlled only by the phospholipid hydroperoxide-reducing enzyme glutathione peroxidase 4 (GPX4)3,4 and radical-trapping antioxidants5,6. However, elucidation of the factors that underlie the sensitivity of a given cell type to ferroptosis7 is crucial to understand the pathophysiological role of ferroptosis and how it may be exploited for the treatment of cancer. Although metabolic constraints8 and phospholipid composition9,10 contribute to ferroptosis sensitivity, no cell-autonomous mechanisms have been identified that account for the resistance of cells to ferroptosis. Here we used an expression cloning approach to identify genes in human cancer cells that are able to complement the loss of GPX4. We found that the flavoprotein apoptosis-inducing factor mitochondria-associated 2 (AIFM2) is a previously unrecognized anti-ferroptotic gene. AIFM2, which we renamed ferroptosis suppressor protein 1 (FSP1) and which was initially described as a pro-apoptotic gene11, confers protection against ferroptosis elicited by GPX4 deletion. We further demonstrate that the suppression of ferroptosis by FSP1 is mediated by ubiquinone (also known as coenzyme Q10, CoQ10): the reduced form, ubiquinol, traps lipid peroxyl radicals that mediate lipid peroxidation, whereas FSP1 catalyses the regeneration of CoQ10 using NAD(P)H. Pharmacological targeting of FSP1 strongly synergizes with GPX4 inhibitors to trigger ferroptosis in a number of cancer entities. In conclusion, the FSP1–CoQ10–NAD(P)H pathway exists as a stand-alone parallel system, which co-operates with GPX4 and glutathione to suppress phospholipid peroxidation and ferroptosis. In the absence of GPX4, FSP1 regenerates ubiquinol from the oxidized form, ubiquinone, using NAD(P)H and suppresses phospholipid peroxidation and ferroptosis in cells.

/pdf/fsp1-is-a-glutathione-independent-ferroptosis-suppressor-1x4r91fxkc.pdf

FSP1 is a glutathione-independent ferroptosis suppressor

The research field of ferroptosis has seen exponential growth over the past few years, since the term was coined in 2012. This unique modality of cell death, driven by iron-dependent phospholipid peroxidation, is regulated by multiple cellular metabolic pathways, including redox homeostasis, iron handling, mitochondrial activity and metabolism of amino acids, lipids and sugars, in addition to various signalling pathways relevant to disease. Numerous organ injuries and degenerative pathologies are driven by ferroptosis. Intriguingly, therapy-resistant cancer cells, particularly those in the mesenchymal state and prone to metastasis, are exquisitely vulnerable to ferroptosis. As such, pharmacological modulation of ferroptosis, via both its induction and its inhibition, holds great potential for the treatment of drug-resistant cancers, ischaemic organ injuries and other degenerative diseases linked to extensive lipid peroxidation. In this Review, we provide a critical analysis of the current molecular mechanisms and regulatory networks of ferroptosis, the potential physiological functions of ferroptosis in tumour suppression and immune surveillance, and its pathological roles, together with a potential for therapeutic targeting. Importantly, as in all rapidly evolving research areas, challenges exist due to misconceptions and inappropriate experimental methods. This Review also aims to address these issues and to provide practical guidelines for enhancing reproducibility and reliability in studies of ferroptosis. Finally, we discuss important concepts and pressing questions that should be the focus of future ferroptosis research.

Ferroptosis: mechanisms, biology and role in disease.

https://minerva-access.unimelb.edu.au/bitstream/handle/11343/194901/Stockwell_Cell_review+2017.pdf

Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease

Objective: To confirm results from the Phase 1 study of CuATSM in sALS Background: A previously reported phase 1 dose-finding study suggested CuATSM may have disease modifying benefit in patients with sporadic ALS (sALS). Over 24 weeks treatment at the recommended phase 2 dose (RP2D) of 72 mg/day, there was a slow rate of disease progression and increased ECAS score. A phase 2a cohort was treated at the RP2D to discover whether these positive results could be replicated. Design/Methods: Study CMD-2016-001 was a first-in-man, multicenter, open-label dose-escalation study in sALS with disease duration ≤3 years. In phase 1, successive cohorts of patients (n=6) were evaluated following a single dose, followed by a 4-week repeated dose study. At investigator discretion, treatment was continued for up to six 4-week cycles. In phase 2a, an expansion cohort (n=15) received up to six 4-week cycles at the RP2D of 72 mg/day determined in Phase 1. Efficacy assessments (ASLFRS-R, ECAS, FVC) were conducted at baseline and after 1 and 6 cycles in Phase 1 and after 1, 2, 4 and 6 cycles in phase 2a. Phase 2a used ECAS A-B-C to avoid practice effects. Results: All patients treated at RP2D had sALS; 0/4 in Phase 1 and 5/15 in Phase 2a had bulbar onset. ALSFRS-R decrease was 0.5 points/month for all 19 subjects. Non-bulbar cases in Phase 1 and 2a had comparable mean change in ALSFRS-R over 24 weeks (−0.4 versus −0.3 points/month). ECAS A-B-C score increased by +7.8 points (p = 0.02) which is comparable to the ECAS increase in the Phase 1 cohort (+10.25). Conclusions: Marked CuATSM treatment effects on disease severity and cognitive function relative to historical controls were observed in sALS in both phase 1 and phase 2a cohorts. These results stimulated the ongoing multicenter, randomized, double-blinded, placebo-controlled study to definitively establish the efficacy of CuATSM. Disclosure: Dr. Rowe has nothing to disclose. Dr. Mathers has nothing to disclose. Dr. Noel has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Collaborative Medicinal Development LLC. Dr. Rosenfeld has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Collaborative Medicinal Development LLC.

Craig S. Rosenfeld

Papers

Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease

CuATSM Phase 2a Study Confirms Disease-Modifying Effects in Patients with Sporadic ALS Observed in the Phase 1 Study (1338)