A Trypanosomatid Iron Transporter that Regulates Mitochondrial Function Is Required for Leishmania amazonensis Virulence

摘要: Iron, an essential co-factor of respiratory chain proteins, is critical for mitochondrial function and maintenance its redox balance. We previously reported a role iron uptake in differentiation Leishmania amazonensis into virulent amastigotes, by mechanism that involves reactive oxygen species (ROS) production independent the classical pH temperature cues. Iron import mitochondria was proposed to be this process, but evidence supporting hypothesis lacking because transporter unknown. Here we describe MIT1, homolog importer genes mrs3 (yeast) mitoferrin-1 (human) highly conserved among trypanosomatids. MIT1 expression survival Trypanosoma brucei procyclic not bloodstream forms, which lack functional complexes. L. LMIT1 null mutants could generated, suggesting promastigote viability. Promastigotes one allele (LMIT1/Δlmit1) showed growth defects were more susceptible ROS toxicity, consistent with as trypanosomatid superoxide dismutases. LMIT1/Δlmit1 metacyclic promastigotes unable replicate intracellular amastigotes after infecting macrophages or cause cutaneous lesions mice. When induced differentiate axenically strong content mitochondria, upregulate ROS-regulatory enzyme FeSOD, changes suggestive imbalance. Our results demonstrate importance parasites, highlight iron-regulated process orchestrates infective amastigotes.