Leishmania donovani iron superoxide dismutase A is targeted to the mitochondria by its N-terminal positively charged amino acids

Getachew, Fitsum; Gedamu, Lashitew

doi:10.1016/j.molbiopara.2007.04.007

Cited by 30 publications

(18 citation statements)

References 32 publications

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“…Leishmania encodes a mitochondrial iron superoxide dismutase (FeSODA) that detoxifies superoxide radicals into oxygen and hydrogen peroxide, 29 which are further reduced by peroxidases. 30 DDX3 (−/−) parasites showed a slight but significant increase in SOD activity that was higher in the presence of menadione, a known inducer of intracellular superoxide production (Figure 2d).…”

Section: Resultsmentioning

confidence: 99%

DDX3 DEAD-box RNA helicase plays a central role in mitochondrial protein quality control in Leishmania

et al. 2016

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DDX3 is a highly conserved member of ATP-dependent DEAD-box RNA helicases with multiple functions in RNA metabolism and cellular signaling. Here, we describe a novel function for DDX3 in regulating the mitochondrial stress response in the parasitic protozoan Leishmania. We show that genetic inactivation of DDX3 leads to the accumulation of mitochondrial reactive oxygen species (ROS) associated with a defect in hydrogen peroxide detoxification. Upon stress, ROS production is greatly enhanced, causing mitochondrial membrane potential loss, mitochondrial fragmentation, and cell death. Importantly, this phenotype is exacerbated upon oxidative stress in parasites forced to use the mitochondrial oxidative respiratory machinery. Furthermore, we show that in the absence of DDX3, levels of major components of the unfolded protein response as well as of polyubiquitinated proteins increase in the parasite, particularly in the mitochondrion, as an indicator of mitochondrial protein damage. Consistent with these findings, immunoprecipitation and mass-spectrometry studies revealed potential interactions of DDX3 with key components of the cellular stress response, particularly the antioxidant response, the unfolded protein response, and the AAA-ATPase p97/VCP/Cdc48, which is essential in mitochondrial protein quality control by driving proteosomal degradation of polyubiquitinated proteins. Complementation studies using DDX3 deletion mutants lacking conserved motifs within the helicase core support that binding of DDX3 to ATP is essential for DDX3's function in mitochondrial proteostasis. As a result of the inability of DDX3-depleted Leishmania to recover from ROS damage and to survive various stresses in the host macrophage, parasite intracellular development was impaired. Collectively, these observations support a central role for the Leishmania DDX3 homolog in preventing ROS-mediated damage and in maintaining mitochondrial protein quality control.

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Section: Resultsmentioning

confidence: 99%

DDX3 DEAD-box RNA helicase plays a central role in mitochondrial protein quality control in Leishmania

et al. 2016

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“…In fact, Leishmania mitochondria produce superoxide and parasite iron superoxide dismutase localises to this organelle in L. donovani [31]. Besides, DETC can also form a complex with Fe 2+ [32], which might lead to inhibition of enzyme activity of iron superoxide dismutase in Leishmania spp.…”

Section: Discussionmentioning

confidence: 99%

DETC Induces Leishmania Parasite Killing in Human In Vitro and Murine In Vivo Models: A Promising Therapeutic Alternative in Leishmaniasis

et al. 2010

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BackgroundChemotherapy remains the primary tool for treatment and control of human leishmaniasis. However, currently available drugs present serious problems regarding side-effects, variable efficacy, and cost. Affordable and less toxic drugs are urgently needed for leishmaniasis.Methodology/Principal FindingsWe demonstrate, by microscopy and viability assays, that superoxide dismutase inhibitor diethyldithiocarbamate (DETC) dose-dependently induces parasite killing (p<0.001) and is able to “sterilize” Leishmania amazonensis infection at 2 mM in human macrophages in vitro. We also show that DETC-induced superoxide production (p<0.001) and parasite destruction (p<0.05) were reverted by the addition of the antioxidant N-acetylcysteine, indicating that DETC-induced killing occurs through oxidative damage. Furthermore, ultrastructural analysis by electron microscopy demonstrates a rapid and highly selective destruction of amastigotes in the phagosome upon DETC treatment, without any apparent damage to the host cell, including its mitochondria. In addition, DETC significantly induced parasite killing in Leishmania promastigotes in axenic culture. In murine macrophages infected with Leishmania braziliensis, DETC significantly induced in vitro superoxide production (p = 0.0049) and parasite killing (p = 0.0043). In vivo treatment with DETC in BALB/C mice infected with Leishmania braziliensis caused a significant decrease in lesion size (p<0.0001), paralleled by a 100-fold decrease (p = 0.0087) in parasite burden.Conclusions/SignificanceDue to its strong leishmanicidal effect in human macrophages in vitro, its in vivo effectiveness in a murine model, and its previously demonstrated in vivo safety profile in HIV treatment, DETC treatment might be considered as a valuable therapeutic option in human leishmaniasis, including HIV/Leishmania co-infection.

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“…In contrast, all Leishmania SODs (FeSODA and FeSODB1/B2) exclusively use iron as a cofactor essential for functionality (Taylor and Kelly, 2010). FeSODA corresponds to the mitochondrial isoform (Getachew and Gedamu, 2007), whereas FeSODB1/B2, which is equivalent to the cytosolic enzyme from higher eukaryotes, appears to be localized in glycosomes (Plewes et al, 2003). Consistent with this view, FeSOD plays an important role in the virulence and intracellular survival of L. donovani, L. tropica, and L. chagasi (Ghosh et al, 2003;Plewes et al, 2003).…”

Section: Downloaded Frommentioning

confidence: 75%

PARing down EAE

Epps¹

2006

The Journal of Experimental Medicine

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Leishmania donovani iron superoxide dismutase A is targeted to the mitochondria by its N-terminal positively charged amino acids

Cited by 30 publications

References 32 publications

DDX3 DEAD-box RNA helicase plays a central role in mitochondrial protein quality control in Leishmania

DDX3 DEAD-box RNA helicase plays a central role in mitochondrial protein quality control in Leishmania

DETC Induces Leishmania Parasite Killing in Human In Vitro and Murine In Vivo Models: A Promising Therapeutic Alternative in Leishmaniasis

PARing down EAE

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