Abstract
Iron, an essential co-factor of respiratory chain proteins, is critical for mitochondrial function and maintenance of its redox balance. We previously reported a role for iron uptake in differentiation of Leishmania amazonensis into virulent amastigotes, by a mechanism that involves reactive oxygen species (ROS) production and is independent of the classical pH and temperature cues. Iron import into mitochondria was proposed to be essential for this process, but evidence supporting this hypothesis was lacking because the Leishmania mitochondrial iron transporter was unknown. Here we describe MIT1, a homolog of the mitochondrial iron importer genes mrs3 (yeast) and mitoferrin-1 (human) that is highly conserved among trypanosomatids. MIT1 expression was essential for the survival of Trypanosoma brucei procyclic but not bloodstream forms, which lack functional respiratory complexes. L. amazonensis LMIT1 null mutants could not be generated, suggesting that this mitochondrial iron importer is essential for promastigote viability. Promastigotes lacking one LMIT1 allele (LMIT1/Δlmit1) showed growth defects and were more susceptible to ROS toxicity, consistent with the role of iron as the essential co-factor of trypanosomatid mitochondrial superoxide dismutases. LMIT1/Δlmit1 metacyclic promastigotes were unable to replicate as intracellular amastigotes after infecting macrophages or cause cutaneous lesions in mice. When induced to differentiate axenically into amastigotes, LMIT1/Δlmit1 showed strong defects in iron content and function of mitochondria, were unable to upregulate the ROS-regulatory enzyme FeSOD, and showed mitochondrial changes suggestive of redox imbalance. Our results demonstrate the importance of mitochondrial iron uptake in trypanosomatid parasites, and highlight the role of LMIT1 in the iron-regulated process that orchestrates differentiation of L. amazonensis into infective amastigotes.
Highlights
Leishmania spp., parasitic protozoa from the Trypanosomatidae family, cause a broad spectrum of human diseases collectively referred to as leishmaniasis
Leishmaniasis is a serious parasitic disease that affects 12 million people worldwide, with clinical manifestations ranging from self-healing cutaneous lesions to deadly visceralizing disease
Following introduction into vertebrate hosts during a sand fly blood meal, Leishmania parasites undergo extensive changes in morphology and metabolism that are critical for adaptation to life inside host macrophages and replication as amastigotes
Summary
Leishmania spp., parasitic protozoa from the Trypanosomatidae family, cause a broad spectrum of human diseases collectively referred to as leishmaniasis. When ingested by sand flies during a bloodmeal, amastigotes transform into flagellated promastigotes that replicate in the insect’s digestive tract. As they mature, promastigotes cease to replicate, transform into infective metacyclic stages and migrate to the fly proboscis, from where they are reintroduced into a mammalian host during a blood meal. Promastigotes cease to replicate, transform into infective metacyclic stages and migrate to the fly proboscis, from where they are reintroduced into a mammalian host during a blood meal To adapt to these distinct environmental conditions, Leishmania undergo extensive morphological changes and metabolic retooling, orchestrated through genome-wide changes in gene expression and posttranslational modifications [2, 3]. The signaling pathway driving the generation of virulent amastigotes, the most important life cycle form in human infections, is still poorly understood
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