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Property "Has-20abstract" (as page type) with input value "The-20mitochondrial-20Ca-3Csup-3E2+-3C-2Fsup-3E-20uptake-20in-20trypanosomatids,-20which-20belong-20to-20the-20eukaryotic-20supergroup-20Excavata,-20shares-20biochemical-20characteristics-20with-20that-20of-20animals,-20which,-20together-20with-20fungi,-20belong-20to-20the-20supergroup-20Opisthokonta.-20However,-20the-20composition-20of-20the-20mitochondrial-20calcium-20uniporter-20(MCU)-20complex-20in-20trypanosomatids-20is-20quite-20peculiar,-20suggesting-20lineage-2Dspecific-20adaptations.-20In-20this-20work,-20we-20used-20-27-27Trypanosoma-20cruzi-27-27-20to-20study-20the-20role-20of-20orthologs-20for-20mitochondrial-20calcium-20uptake-201-20(MICU1)-20and-20MICU2-20in-20mitochondrial-20Ca-3Csup-3E2+-3C-2Fsup-3E-20uptake.-20-27-27T.-20cruzi-27-27-20MICU1-20(TcMICU1)-20and-20TcMICU2-20have-20mitochondrial-20targeting-20signals,-20two-20canonical-20EF-2Dhand-20calcium-2Dbinding-20domains,-20and-20localize-20to-20the-20mitochondria.-20Using-20the-20CRISPR-2FCas9-20system-20(i.e.,-20clustered-20regularly-20interspaced-20short-20palindromic-20repeats-20with-20Cas9),-20we-20generated-20TcMICU1-20and-20TcMICU2-20knockout-20(-2DKO)-20cell-20lines.-20Ablation-20of-20either-20TcMICU1-20or-20TcMICU2-20showed-20a-20significantly-20reduced-20mitochondrial-20Ca-3Csup-3E2+-3C-2Fsup-3E-20uptake-20in-20permeabilized-20epimastigotes-20without-20dissipation-20of-20the-20mitochondrial-20membrane-20potential-20or-20effects-20on-20the-20AMP-2FATP-20ratio-20or-20citrate-20synthase-20activity.-20However,-20none-20of-20these-20proteins-20had-20a-20gatekeeper-20function-20at-20low-20cytosolic-20Ca-3Csup-3E2+-3C-2Fsup-3E-20concentrations-20(-5BCa-3Csup-3E2+-3C-2Fsup-3E-5D-3Csub-3Ecyt-3C-2Fsub-3E),-20as-20occurs-20with-20their-20mammalian-20orthologs.-20TcMICU1-2DKO-20and-20TcMICU2-2DKO-20epimastigotes-20had-20a-20lower-20growth-20rate-20and-20impaired-20oxidative-20metabolism,-20while-20infective-20trypomastigotes-20have-20a-20reduced-20capacity-20to-20invade-20host-20cells-20and-20to-20replicate-20within-20them-20as-20amastigotes.-20The-20findings-20of-20this-20work,-20which-20is-20the-20first-20to-20study-20the-20role-20of-20MICU1-20and-20MICU2-20in-20organisms-20evolutionarily-20distant-20from-20animals,-20suggest-20that,-20although-20these-20components-20were-20probably-20present-20in-20the-20last-20eukaryotic-20common-20ancestor-20(LECA),-20they-20developed-20different-20roles-20during-20evolution-20of-20different-20eukaryotic-20supergroups.-20The-20work-20also-20provides-20new-20insights-20into-20the-20adaptations-20of-20trypanosomatids-20to-20their-20particular-20life-20styles.-0A-0A-27-27Trypanosoma-20cruzi-27-27-20is-20the-20etiologic-20agent-20of-20Chagas-20disease-20and-20belongs-20to-20the-20early-2Dbranching-20eukaryotic-20supergroup-20Excavata.-20Its-20mitochondrial-20calcium-20uniporter-20(MCU)-20subunit-20shares-20similarity-20with-20the-20animal-20ortholog-20that-20was-20important-20to-20discover-20its-20encoding-20gene.-20In-20animal-20cells,-20the-20MICU1-20and-20MICU2-20proteins-20act-20as-20Ca-3Csup-3E2+-3C-2Fsup-3E-20sensors-20and-20gatekeepers-20of-20the-20MCU,-20preventing-20Ca-3Csup-3E2+-3C-2Fsup-3E-20uptake-20under-20resting-20conditions-20and-20favoring-20it-20at-20high-20cytosolic-20Ca-3Csup-3E2+-3C-2Fsup-3E-20concentrations-20(-5BCa-3Csup-3E2+-3C-2Fsup-3E-5D-3Csub-3Ecyt-3C-2Fsub-3E).-20Using-20the-20CRISPR-2FCas9-20technique,-20we-20generated-20TcMICU1-20and-20TcMICU2-20knockout-20cell-20lines-20and-20showed-20that-20MICU1-20and-20-2D2-20do-20not-20act-20as-20gatekeepers-20at-20low-20-5BCa-3Csup-3E2+-3C-2Fsup-3E-5D-3Csub-3Ecyt-3C-2Fsub-3E-20but-20are-20essential-20for-20normal-20growth,-20host-20cell-20invasion,-20and-20intracellular-20replication,-20revealing-20lineage-2Dspecific-20adaptations.-0A-0A-3Csmall-3ECopyright-20©-202019-20Bertolini-20et-20al.-3C-2Fsmall-3E" contains invalid characters or is incomplete and therefore can cause unexpected results during a query or annotation process.

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