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Property "Has-20abstract" (as page type) with input value "-5B-5BImage-2D3AMITOEAGLE-2Dlogo.jpg-7Cleft-7C100px-7Clink=http-2D3A-2F-2Fwww.mitoglobal.org-2Findex.php-2FMITOEAGLE-7CCOST-20Action-20MITOEAGLE-5D-5D-0AWithin-20a-20drug-20discovery-20program-20derived-20from-20a-20project-20for-20a-20pharmacological-20treatment-20of-20mitochondrial-20complex-20I-20deficiency,-20we-20have-20developed-20cell-2Dpermeable-20prodrugs-20of-20succinate-20(NV118)-20and-20malonate-20(NV161)-20suitable-20for-20research-20use-20in-20intact-20cells.-20Succinate-20is-20an-20intermediate-20of-20the-20Krebs’-20cycle-20and-20acts-20as-20mitochondrial-20energy-20substrate-20by-20providing-20reducing-20equivalents-20to-20complex-20II-20(succinate-20dehydrogenase)-20of-20the-20mitochondrial-20oxidative-20phosphorylation-20pathway.-20As-20succinate-20is-20converted-20to-20malate-20by-20complex-20II,-20electrons-20are-20transferred-20down-20the-20pathway-20leading-20to-20proton-20pumping-20and-20ATP-2Dsynthesis.-20Succinate,-20as-20a-20dicarboxylic-20acid,-20is-20not-20cell-2Dpermeable-20and-20for-20exogenous-20succinate-20to-20enter-20cells-20the-20cell-20membrane-20requires-20permeabilization,-20using-20e.g.-20digitonin-20or-20perfringolysin.-20NV118-20allows-20the-20researcher-20to-20deliver-20succinate-20to-20the-20cytoplasm-20without-20disrupting-20the-20plasma-20membrane.-20Malonate-20is-20a-20competitive-20inhibitor-20of-20complex-20II-20that-20binds-20to-20the-20active-20site-20of-20succinate-20dehydrogenase,-20thus-20preventing-20succinate-20from-20being-20metabolized.-20Like-20succinate,-20malonate-20is-20a-20dicarboxylic-20acid-20that-20does-20not-20readily-20permeate-20through-20the-20cell-20membrane.-20By-20using-20the-20same-20prodrug-20strategy-20as-20for-20NV118,-20the-20cell-2Dpermeable-20analogue-20of-20malonate,-20NV161,-20has-20been-20synthesized.-20NV118-20and-20NV161-20are-20rapidly-20metabolized,-20likely-20by-20the-20action-20of-20carboxyesterases,-20releasing-20succinate-20and-20malonate-20respectively.-20-0A-0ACell-2Dpermeable-20succinate-20and-20malonate-20were-20tested-20in-20a-20range-20of-20human-20cells-20and-20tissues,-20such-20as-20blood-20cells,-20fibroblasts,-20immortalized-20liver-20cells-20and-20human-20heart-20fibers-20either-20in-20the-20Oroboros-20O2k-2DFluoRespirometer-20(Oroboros-20Instruments,-20Innsbruck,-20Austria)-20or-20in-20the-20Seahorse-20Bioscience-20XFe96-20Extracellular-20Flux-20Analyser-20(Seahorse-20Bioscience,-20North-20Billerica,-20USA).-20Dose-2Dresponse-20curves-20for-20both-20prodrugs-20were-20obtained-20in-20human-20complex-20I-20inhibited-20platelets-20and-20primary-20fibroblasts.-0A-0ANV118-20and-20NV161-20dose-2Ddependently-20support-20and-20inhibit-20succinate-2Dlinked-20mitochondrial-20respiration-20in-20intact-20human-20platelets-20and-20fibroblasts.-20NV161-20completely-20inhibits-20succinate-2Dlinked-20mitochondrial-20respiration-20at-20about-20ten-20times-20lower-20concentration-20as-20compared-20to-20malonate.-20Dimethyl-20succinate-20and-20dimethyl-20malonate-20have-20previously-20been-20reported-20to-20be-20cell-2Dpermeable,-20but-20did-20not-20show-20strong-20evidence-20of-20efficient-20cell-20penetration-20in-20this-20study.-0A-0AWe-20believe-20that-20NV118-20and-20NV161-20may-20prove-20valuable-20as-20scientific-20tools-20in-20mitochondrial-20research,-20enabling-20evaluation-20of-20complex-20II-20in-20intact-20cells-20and-20tissues.-20Analogues-20of-20both-20the-20succinate-20and-20malonate-20series-20optimized-20for-20-27-27in-20vivo-27-27-20use-20are-20simultaneously-20being-20developed.-0A-0A-2D3A-2D3A-5Bhttp-2D3A-2F-2Fbioblast.at-2Fimages-2F0-2F0f-2FAasander_Frostner_Poster_MiP2017.pdf-20-27-27'Poster-20link-27-27'-5D" contains invalid characters or is incomplete and therefore can cause unexpected results during a query or annotation process.

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