Plants, animals and fungi all belong to a group of organisms known as eukaryotes. Their cells host a variety of compartments, with each having a specific role. For example, mitochondria are tasked with providing the energy that powers most of the processes that keep the cell alive. Membranes delimit these compartments, as well as the cells themselves.

Iron is an element needed for chemical reactions that are essential for the cell to survive. Yet, the byproducts of these reactions can damage – ‘oxidize’ – the lipid molecules that form the cell’s membranes, including the one around mitochondria. Unless enzymes known as peroxidases come to repair the oxidized lipids, the cell dies in a process called ferroptosis. Scientists know that this death mechanism is programmed into the cells of humans and other complex eukaryotes.

However, Bogacz and Krauth-Siegel wanted to know if ferroptosis also exists in creatures that appeared early in the evolution of eukaryotes, such as the trypanosome Trypanosoma brucei. This single-cell parasite causes sleeping sickness in humans and a disease called nagana in horses and cattle. Before it infects a mammal, T. brucei goes through an ‘insect stage’ where it lives in the tsetse fly; there, it relies on its mitochondrion to produce energy.

Bogacz and Krauth-Siegel now show that if the parasites in the insect stage do not have a specific type of peroxidases, they die within a few hours. In particular, problems in the membranes of the mitochondrion stop the compartment from working properly. These peroxidases-free trypanosomes fare better if they are exposed to molecules that prevent iron from taking part in the reactions that can harm lipids. They also survive more if they are forced to create large amounts of an enzyme that relies on iron to protect the mitochondrion against oxidation. Finally, using drugs that prevent ferroptosis in human cells completely rescues these trypanosomes. Taken together, the results suggest that ferroptosis is an ancient cell death program which exists in T. brucei; and that, in the insect stage of the parasite's life cycle, this process first damages the mitochondrion.

This last finding could be particularly relevant because the role of mitochondria in ferroptosis in mammals is highly debated. Yet, most of the research is done in cells that do not rely on this cellular compartment to get their energy. During their life cycle, trypanosomes are either dependent on their mitochondria, or they can find their energy through other sources: this could make them a good organism in which to dissect the precise mechanisms of ferroptosis.

Ferroptosis is characterized by the iron-dependent accumulation of cellular lipid hydroperoxides to lethal levels. This form of regulated cell death has been implicated in the pathology of degenerative diseases (e.g. Alzheimer’s, Huntington’s and Parkinson’s diseases), cancer, ischemia-reperfusion injury and kidney degeneration (for recent reviews see [Doll and Conrad, 2017; Stockwell et al., 2017; Galluzzi et al., 2018]). The term ferroptosis was coined in 2012 to describe a form of death in cancer cells induced by the small molecule erastin (Dixon et al., 2012; Dixon et al., 2014; Cao and Dixon, 2016). Consequence is an inhibition of glutathione biosynthesis and thus of glutathione peroxidase 4 (GPx4) activity. Of the eight glutathione peroxidases in mammalian cells, GPx4 is the only one that is able to detoxify lipid hydroperoxides even within membranes (Thomas et al., 1990; Seiler et al., 2008; Brigelius-Flohé and Maiorino, 2013). Inactivation of GPx4 by chemicals like for example RSL3 induces ferroptosis (Yang et al., 2014); and inducible GPx4-deletion in mice revealed that ferroptosis is a pervasive and dynamic form of cell death also in non-transformed cells (Friedmann Angeli et al., 2014). Heat-stressed plants can also undergo a ferroptosis-like cell death (Distéfano et al., 2017). A hallmark of a cell death occurring exclusively by ferroptosis is its suppression by iron chelators (Dixon et al., 2012) or lipophilic antioxidants (Seiler et al., 2008; Krainz et al., 2016) as well as by the depletion of polyunsaturated fatty acids in membrane lipids (Doll et al., 2017; Kagan et al., 2017).

African trypanosomes (Trypanosoma brucei species) are the causative agents of human sleeping sickness and Nagana cattle disease. The obligate free living protozoan parasites multiply as bloodstream (BS) form in the mammalian host and as procyclic (PC) form in the tsetse fly vector. BS T. brucei rely exclusively on glycolysis for energy supply and have an only rudimentary mitochondrion, whereas in the PC stage, the single mitochondrion is fully elaborated and the parasites gain ATP via oxidative phosphorylation. Trypanosomes have an unusual thiol redox metabolism that is based on trypanothione [N¹, N⁸-bis(glutathionyl)spermidine, T(SH)₂)] and the flavoenzyme trypanothione reductase (TR) (Krauth-Siegel and Leroux, 2012; Manta et al., 2013; Manta et al., 2018). The trypanothione system delivers the reducing equivalents for a variety of crucial pathways. Most of the reactions are mediated by tryparedoxin (Tpx), an essential distant member of the thioredoxin protein family (Comini et al., 2007). Trypanosomes lack catalase. Hydroperoxides are detoxified by 2-Cys-peroxiredoxins (Tetaud et al., 2001; Budde et al., 2003; Wilkinson et al., 2003) and non-selenium glutathione peroxidase-type (Px) enzymes (Hillebrand et al., 2003; Wilkinson et al., 2003; Schlecker et al., 2005). Whereas the peroxiredoxins use hydrogen peroxide and peroxynitrite as main substrates (Thomson et al., 2003; Trujillo et al., 2004), the Px-type enzymes preferably detoxify lipid-derived hydroperoxides (Diechtierow and Krauth-Siegel, 2011). With NADPH as ultimate electron donor, the reducing equivalents flow via TR, T(SH)₂, and tryparedoxin onto the peroxidases which therefore have been named tryparedoxin peroxidases (Castro and Tomás, 2008; Krauth-Siegel and Comini, 2008; Krauth-Siegel and Leroux, 2012; Manta et al., 2013).

Tandemly arranged genes encode three virtually identical Px-type enzymes (Px I, II, and III) in T. brucei (Hillebrand et al., 2003). RNA-interference against the Px-type enzymes results in a severe growth defect in both BS and PC T. brucei (Wilkinson et al., 2003; Schlecker et al., 2005). Proliferation of the Px-depleted BS parasites can, however, be restored by supplementing the medium with the vitamin E-analog Trolox [(±)−6-hydroxy-2,5,7,8-tetramethylchromane-2-carboxylic acid] (Diechtierow and Krauth-Siegel, 2011). The same is true for cells lacking GPx4, the closest related enzyme in mammals (Seiler et al., 2008). Selective knockout (KO) of the gene encoding the mitochondrial Px III has only a mild and transient effect on the in vitro proliferation of BS T. brucei and the mutant parasites are fully infectious in the mouse model. In contrast, cells that lack the cytosolic peroxidases Px I and II die after transfer into Trolox-free medium (Diechtierow and Krauth-Siegel, 2011; Hiller et al., 2014). The lethal phenotype of the BS parasites starts at the lysosome and is closely linked to the endocytosis of iron-loaded host transferrin (Hiller et al., 2014).

In the PC insect stage of T. brucei, the presence of either the cytosolic or the mitochondrial peroxidases is sufficient for viability. However, deletion of the complete peroxidase (px I-III) locus is lethal. The cell death can be reverted by exogenous Trolox, deferoxamine (Dfx) or MitoQ which suggested an iron-induced lipid peroxidation that may start at the mitochondrion (Schaffroth et al., 2016). Here we show that the death program in the peroxidase-deficient PC T. brucei closely resembles ferroptosis in mammalian cells. Integrity and viability of the parasites are preserved by known ferroptosis inhibitors. Strikingly, sensors for mitochondrial oxidants and chelatable iron as well as overexpression of an iron-dependent superoxide dismutase in the mitochondrion attenuate cell lysis. Transmission electron microscopy of the Px I-III knockout (KO) cells reveals mitochondrial matrix condensation and formation of enlarged cristae. Our data show that oxidants and iron in the mitochondrial matrix play a critical role in the process and that ferroptosis is an evolutionary ancient cell death program that is prevented by distant thiol peroxidases.

Here we report that trypanosomes that lack the lipid hydroperoxide-detoxifying tryparedoxin peroxidases undergo a cell death which is suppressed by iron chelation (Dfx) or lipophilic antioxidants (Trolox, α-Toc, Lpx-1, Fer-1) and involves accumulation of lipid hydroperoxides and thus fulfils all criteria defining ferroptosis (Stockwell et al., 2017; Galluzzi et al., 2018). The first alterations observed after transfer of Px I-III-deficient PC parasites into medium without protecting agent were mitochondrial lipid peroxidation, loss of the mitochondrial membrane potential, drop of cellular ATP and production of mitochondrial oxidants indicating that in these cells the ferroptosis-type death started at the mitochondrion. The implication of mitochondria in ferroptosis is still highly controversial and debated in the mammalian system. Human cancer cells undergoing erastin-induced ferroptosis retain normal ATP levels; and cells that lack a functional electron transport chain or are depleted of mitochondria can experience ferroptosis (Dixon et al., 2012; Gaschler et al., 2018). Clearly, an active mitochondrial electron transport chain is not a prerequisite for a cell to undergo ferroptosis. Yet, even in these cells, morphological changes such as the formation of smaller mitochondria with increased membrane density were observed (Dixon et al., 2012).

GPx4-deficient mouse embryonic fibroblasts (Pfa1 cells) show a breakdown of the mitochondrial membrane potential (Seiler et al., 2008), but initial lipid peroxidation occurs outside the mitochondrial matrix and involves a disruption of the outer mitochondrial membrane (Friedmann Angeli et al., 2014). In redox phospholipidomics, GPx4-inactivated Pfa 1 cells revealed increased levels of oxygenated derivatives for all major classes of phospholipids, with the exception of cardiolipin and lipid peroxidation was found to take place predominantly in endoplasmic reticulum (ER)-associated sites (Kagan et al., 2017). On the other hand, serum-induced ferroptosis in MEFs under amino acid starvation causes ATP depletion (Gao et al., 2015) and erastin-induced ferroptosis in neuronal cells is accompanied by a loss of the mitochondrial membrane potential and cellular ATP (Neitemeier et al., 2017). Strikingly, GPx4-deficient kidneys display a time-dependent formation of peroxidized cardiolipin (Friedmann Angeli et al., 2014) and mitochondria-targeted nitroxides are able to inhibit ferroptosis in a variety of tissue types and across multiple growth conditions demonstrating that mitochondrial lipid oxidation is critical in promoting the ferroptotic cell death (Krainz et al., 2016).

The mitochondrial phenotype of the peroxidase-deficient PC T. brucei is not a specialized property of these protozoa and their single mitochondrion. In the mammalian bloodstream form – which relies exclusively on glycolysis for energy supply and acquires iron by endocytosis of host transferrin – lack of the cytosolic peroxidases triggers an iron-dependent lipid peroxidation and cell death that originates at the lysosome (Hiller et al., 2014). A respective phenotype has been reported for human fibrosarcoma HT 1080 cells or lung cancer Calu-1 cells which are protected from erastin toxicity by inhibitors of lysosomal activities (Torii et al., 2016). Our results strongly suggest that ferroptosis can be initiated at distinct subcellular sites. The role of mitochondria in ferroptosis execution appears to depend on the individual cell type and even the culture conditions such as the use of high glucose medium. A crucial factor could be that rapidly proliferating cells such as many cancer and embryonic cells rely more on glycolysis whereas differentiated cells primarily use oxidative phosphorylation for ATP production. In addition, ferroptosis starting at one cellular compartment may rapidly spread to other sites. Lipid transport proteins disseminate oxidative stress between compartments by preferably trafficking peroxidized lipids to mitochondria (Kriska et al., 2010; Vila et al., 2004; Friedmann Angeli et al., 2014).

After loss of the mitochondrial membrane potential, Px I-III-deficient cells still displayed a tubular staining for VDAC, an integral protein of the outer mitochondrial membrane. The most prominent alterations revealed by electron microscopy were a condensation of the mitochondrial matrix and appearance of white blebs which probably reflect enlarged cristae. A rupture of the outer membrane, described for mammalian cells after inactivation of GPx4 (Friedmann Angeli et al., 2014; Doll et al., 2017), was not observed. In accordance with the situation in ferroptotic mammalian cells, other subcellular structures, and in particular the nucleus, remained unaffected (Stockwell et al., 2017). In the absence of a protecting agent, the cytosol of the Px I-III-deficient parasites became progressively lighter due to swelling of the cell body which finally resulted in cell death. That mitochondrial membrane peroxidation is an early event in the death of the peroxidase-deficient cells is supported by the finding that MitoPerOx presented a faster oxidation kinetic than the untargeted BODIPY C11 sensor. The inner mitochondrial membrane is particularly susceptible to oxidative damage because of its very large surface area and the proximity to the superoxide-producing respiratory chain and the high content of peroxidation-sensitive unsaturated fatty acids in its phospholipids, notably cardiolipin (Prime et al., 2012). A comparative study on different phospholipids revealed cardiolipin with its two phosphate groups and thus most anionic phospholipid, as strongest binder of GPx4 (Cozza et al., 2017). T. brucei is rich in polyunsaturated fatty acids, with C22:4–6 and C20:2–5 as the most abundant species (Richmond et al., 2010) and also one of the cardiolipin species identified in isolated mitochondria contains a C22:6 fatty acid (Guler et al., 2008). This clearly creates a vulnerability of trypanosomes for membrane oxidation.

As a characteristic feature of cells prone to ferroptosis, the Px I-III-deficient cells retain full viability in the presence of an iron chelator but the subcellular site of the iron involved remained elusive. PC T. brucei lack a transferrin receptor but take up iron from ferric complexes via a 2-step mechanism in which ferric iron is reduced to ferrous iron and is subsequently transported (Mach et al., 2013). The parasites possess Mit1, a homolog of the iron transport protein mitoferrin-1 in the inner mitochondrial membrane of vertebrate cells. Mit1 is essential in PC T. brucei and depletion of its mRNA specifically affects the mitochondrion (Mittra et al., 2016). Here we present several lines of evidence that mitochondrial matrix iron triggers the cell death in the PC Px I-III-deficient trypanosomes. RPA, an iron-chelating sensor that is targeted to the mitochondrion, prolonged viability of the parasites. In Dfx-treated cells the sensor was de-quenched indicating that Dfx lowers the iron available for chelation by RPA. Radiolabeled Dfx was demonstrated not to be retained in the endosomal/lysomal compartments but to accumulate in the soluble/cytosolic fraction of mammalian cells (Hoyes and Porter, 1993). This is supported by our own data. Whereas free and starch-coupled Dfx equally protect BS T. brucei which lack the cytosolic peroxidases and show a lysosomal lethal phenotype, only free, but not starch-coupled Dfx, is able to protect the PC peroxidase-deficient cells (Hiller et al., 2014; Schaffroth et al., 2016). It is very likely that Dfx exerts its iron chelating and thus protecting effects in the cytosol. This could significantly alter our view on the mechanisms of ferroptosis that are partially based on the assumption that Dfx is membrane-impermeable and restricted to the lysosomal compartment (Cao and Dixon, 2016; Gaschler et al., 2018). Upon incubation of the Px I-III KO cells without any protecting agent, the RPA fluorescence became de-quenched, most probably because, due to breakdown of the mitochondrial membrane potential, the sensor leaks out into the cytosol where the chelatable iron concentration is expectedly lower than in the mitochondrial matrix. Further support for the role of matrix iron in the process came from the finding that overexpression of the mitochondrial iron-SODA lowered the Dfx concentration required to protect the peroxidase-deficient cells. Three putative protecting mechanisms could be envisaged: an attenuated generation of free iron from FeS clusters by superoxide, a diminished level of reactive iron by affecting the recycling of Fe²⁺ from Fe³⁺ and incorporation of iron into the newly expressed mitochondrial protein. Each of these mechanisms would lower the reactive iron level in the mitochondrial matrix. To our knowledge this is the first study in which the subcellular site of iron triggering ferroptosis has been identified.

Mechanisms that result in increased levels of poly-unsaturated fatty acids or cellular iron as well as those that decrease the capacity of the cell to detoxify peroxidized lipids such as depletion of GSH or GPx4 are able to trigger ferroptosis. Enzymatic effectors for example lipoxygenases can drive ferroptotic oxidation of poly-unsaturated fatty acids (Seiler et al., 2008; Stockwell et al., 2017). However, the lipoxygenase-mediated lethal effect is observed under GSH depletion conditions but not if ferroptosis is induced by GPx4 inactivation demonstrating that the presence of a lipoxygenase is not essential for the cell death program (Yang et al., 2016). As shown recently for diverse types of lipoxygenase inhibitors, there is a correlation between the anti-ferroptotic activity and reactivity as radical-trapping agents (Shah et al., 2018). Clearly, ferroptosis can be triggered spontaneously for instance by a rise in peroxidized lipids. There is a close link between the cellular lipid composition and ferroptosis sensitivity. ACSL4 (acyl-CoA synthetase long-chain family member 4) is a critical determinant of the membrane lipid composition and sensitizes cells to ferroptosis whereas cells lacking ACSL4 show marked resistance to ferroptosis induction (Doll et al., 2017). The T. brucei genome encodes at least five acyl-CoA synthetases (ACSs). One of the four enzymes studied so far (ACS1) accepts arachidonic acid and 22:6 fatty acids as preferred substrates (Jiang and Englund, 2001) and the so far uncharacterized ACS5 (Tb927.10.3260) has been annotated as putative long-chain-fatty-acid-CoA-ligase. An interesting aspect of future studies will be the putative role of long-chain ASCs in triggering ferroptosis in these protozoa.

As shown here, ferroptosis is not restricted to mammalian cells (Seiler et al., 2008; Dixon et al., 2012; Friedmann Angeli et al., 2014; Stockwell et al., 2017) and plants (Distéfano et al., 2017). The regulated cell death occurs in trypanosomes, one of the earliest branching eukaryotes. The incorporation of polyunsaturated fatty acids into cell membranes was probably highly advantageous during evolution, allowing to modulate the membrane fluidity and functionality of membrane proteins and cells to adapt to different environments and temperatures. This is particularly important for African trypanosomes which during their digenetic life cycle switch between the 37°C bloodstream of a mammalian host and the 27°C midgut of the tsetse fly vector. The presence of poly-unsaturated fatty acids in the membranes, however, requires sophisticated antioxidant systems. In most cells this is achieved by the GSH/GPx4 couple. Trypanosomes developed a defense system that is coupled to the unique trypanothione/tryparedoxin system and replaces the GSH/glutathione peroxidase GPx4 pair.

All data generated or analysed during this study are included in the manuscript and supporting files.

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Author details

1. Marta Bogacz

   Biochemie-Zentrum der Universität Heidelberg, Heidelberg, Germany

   Contribution

   Formal analysis, Validation, Investigation, Visualization, Writing—original draft

   Competing interests

   No competing interests declared

2. R Luise Krauth-Siegel

   Biochemie-Zentrum der Universität Heidelberg, Heidelberg, Germany

   Contribution

   Conceptualization, Resources, Supervision, Funding acquisition, Writing—original draft, Writing—review and editing

   For correspondence

   luise.krauth-siegel@bzh.uni-heidelberg.de

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-2164-8116

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