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Cu is essential for aerobic organisms, but it can also be toxic, and so its transport and storage must be regulated. In the present study, we characterized the effects of changes in Cu availability on growth behavior, intracellular ion content and oxygen consumption. Our results show that copper is essential for epimastigote proliferation and for the metacyclogenesis process. On the other hand, intracellular amastigotes suffered copper stress during infection. In addition, we identify gene products potentially involved in copper metabolism. Orthologs of the highly conserved P\u2010type Cu ATPases involved in copper export and loading of secreted enzymes were identified and named\n                    <jats:italic>T. cruzi<\/jats:italic>\n                    Cu P\u2010type ATPase (\n                    <jats:italic>Tc<\/jats:italic>\n                    CuATPase).\n                    <jats:italic>Tc<\/jats:italic>\n                    CuATPase transcription is upregulated during infective stages and following exposure to copper chelators in the epimastigote stage. Homolog sequences for the high affinity import protein CTR1 were not found. Instead, we propose that the\n                    <jats:italic>T. cruzi<\/jats:italic>\n                    iron transporter (\n                    <jats:italic>Tc<\/jats:italic>\n                    IT), a ZIP family transporter, could be involved in copper uptake based on transcriptional response to copper availability. Further canonical copper targets (based on homology to yeast and mammals) such as the\n                    <jats:italic>T. cruzi<\/jats:italic>\n                    ferric reductase (\n                    <jats:italic>Tc<\/jats:italic>\n                    FR) and the cupro\u2010oxidase\n                    <jats:italic>Tc<\/jats:italic>\n                    Fet3 are upregulated during infective stages and under conditions of intracellular copper deficiency. In sum, copper metabolism is essential for the life cycle of\n                    <jats:italic>T. cruzi<\/jats:italic>\n                    . Even though cytosolic copper chaperons were not identified, we propose a previously undescribed model for copper transport and intracellular distribution in\n                    <jats:italic>T. cruzi<\/jats:italic>\n                    , including some conserved factors such as\n                    <jats:italic>Tc<\/jats:italic>\n                    CuATPase, as well as others such as\n                    <jats:italic>Tc<\/jats:italic>\n                    FR and\n                    <jats:italic>Tc<\/jats:italic>\n                    IT, playing novel functions.\n                  <\/jats:p>","DOI":"10.1111\/febs.17340","type":"journal-article","created":{"date-parts":[[2024,12,6]],"date-time":"2024-12-06T00:58:36Z","timestamp":1733446716000},"page":"391-411","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Solving the puzzle of copper trafficking in\n                    <i>Trypanosoma cruzi<\/i>\n                  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