Leishmania donovani mitochondrial iron superoxide dismutase A is released into the cytosol during miltefosine induced programmed cell death

Multi-analytical platform metabolomic approach to study miltefosine mechanism of action and resistance in Leishmania

“…In contrast, trypanothione, the ultimate metabolite of the pathway underwent decay, while spermidine and glutathione maintained their levels in ST, which may suggest a feasible inhibition of the final biosynthetic steps of trypanothione or drainage of its intracellular pool. In any case, shortage of trypanothione will increase the vulnerability of the parasite to oxidative stress, caused by increased levels of ROS induced by MT [12], aggravated due to the inhibition of electron flow across the respiratory chain at the level of cytochrome oxidase [24] and impairment of mitochondrial ROS detoxification by the release of superoxide dismutase [23].…”

“…Its molecular properties [16] along with its high intracellular concentration will favor a multitarget lethal mechanism [17]: inhibition of choline transport [18], disturbances in the biosynthesis of ether-lipids [19] and phospholipids with inversion of the phosphatidylcholine (PC)/phosphatidylethanolamine (PE) ratio [20][21][22] and mitochondrial dysfunction with the release of iron superoxide dismutase A into the cytoplasm [23] as well as inhibition of cytochrome c oxidase [24]. Concerning the latter, overexpression of the Cox9 subunit of cytochrome oxidase reverts miltefosine susceptibility and associated cell death [25], although its validation in Leishmania is still missing.…”

Mitochondrial Proteomics of Antimony and Miltefosine Resistant Leishmania infantum

“…The single mitochondrion is one of the major sources of ROS in trypanosomatids through the activity of the mitochondrial electron transport chain (mtETC, depicted as complex I to IV in Figure 3) [35] and SbIII and MIL are known to induce cell death in Leishmania by producing ROS within the mitochondrion in drug-sensitive parasites. A decrease in energy production results in opening of the mitochondrial permeability transition pore (mPTP), which causes collapse of mitochondrial membrane potential (Δψm), mitochondrial membrane swelling, and indirectly enhances the release of death factors (e.g., cytochrome c (Cytc)) into the cytosol, leading to cell death [25,36] (Figure 3). It was demonstrated that SbIII or MIL resistant parasites present significantly lower levels of ROS compared to wild-type cells [13] and this suggests that SbIII and MIL resistant Leishmania are probably able to maintain mitochondrial ROS to a level similar or lower than wild-type, either by more effective scavenging or by decreased ROS production.…”

“…Mitochondria are also involved in the parasite response to pharmacological perturbation, being the main source of ROS and controlling cell death. It has been shown that ROS are produced when Leishmania are treated with either MIL or antimony [12,13,25,26]. Parasites belonging to the Kinetoplastida eukaryotic branch are unusual in that each cell contains one, enlarged mitochondrion, stretching the majority of the length of the cell.…”

Functional analysis of iron superoxide dismutase-A in wild-type and antimony-resistant Leishmania braziliensis and Leishmania infantum lines

“…We conclude that overexpression of FeSOD-A in wild-type lines of L. (V.) braziliensis and L. (L.) infantum increased resistance to SbIII. Getachew and Gedamu [23] reported the role of LdFeSOD-A in the protection of L. (L.) donovani against oxidative stress and in the control of events related to programmed cell death. The authors also showed that overexpression of LdFeSOD-A protects the parasite against cytotoxicity induced by miltefosine and reduces the production of superoxide anion.…”