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Property "Has-20abstract" (as page type) with input value "Eukaryotic-20cell-20metabolism-20consists-20of-20processes-20that-20generate-20available-20energy,-20such-20as-20glycolysis,-20the-20tricarboxylic-20acid-20(TCA)-20cycle-20and-20oxidative-20phosphorylation-20(OXPHOS)-20and-20those-20that-20consume-20it,-20including-20macromolecular-20synthesis,-20the-20maintenance-20of-20ionic-20gradients-20and-20cellular-20detoxification.-20By-20converting-20pyruvate-20to-20acetyl-2DCoA-20(AcCoA),-20the-20pyruvate-20dehydrogenase-20(PDH)-20complex-20(PDC)-20links-20glycolysis-20and-20the-20TCA-20cycle.-20Surprisingly,-20disrupting-20the-20connection-20between-20glycolysis-20and-20the-20TCA-20cycle-20by-20inactivation-20PDC-20has-20only-20minor-20effects-20on-20cell-20replication.-20However,-20the-20molecular-20basis-20for-20this-20metabolic-20re-2Dequilibration-20is-20unclear.-20We-20report-20here-20that-20CRISPR-2FCas9-2Dgenerated-20PDH-2Dknockout-20(PDH-2DKO)-20rat-20fibroblasts-20reprogramed-20their-20metabolism-20and-20their-20response-20to-20short-2Dterm-20c-2DMyc-20(Myc)-20oncoprotein-20overexpression.-20PDH-2DKO-20cells-20replicated-20normally,-20but-20produced-20surprisingly-20little-20lactate.-20They-20also-20exhibited-20higher-20rates-20of-20glycolysis-20and-20OXPHOS.-20-20In-20addition,-20PDH-2DKO-20cells-20showed-20altered-20cytoplasmic-20and-20mitochondrial-20pH,-20redox-20states,-20and-20mitochondrial-20membrane-20potential-20(ΔΨμ).-20Conditionally-20activated-20Myc-20expression-20affected-20some-20of-20these-20parameters-20in-20a-20PDH-2Ddependent-20manner.-20PDH-2DKO-20cells-20had-20increased-20oxygen-20consumption-20rates-20in-20response-20to-20glutamate,-20but-20not-20to-20malate,-20and-20were-20depleted-20in-20all-20TCA-20cycle-20substrates-20between-20α-2Dketoglutarate-20and-20malate-20despite-20high-20rates-20of-20glutaminolysis,-20as-20determined-20by-20flux-20studies-20with-20isotopically-20labeled-20glutamine.-20Malate-20and-20pyruvate-20were-20spanerted-20to-20produce-20aspartate,-20thereby-20potentially-20explaining-20the-20failure-20to-20accumulate-20lactate.-20We-20conclude-20that-20PDH-2DKO-20cells-20maintain-20proliferative-20capacity-20by-20utilizing-20glutamine-20to-20supply-20high-20rates-20of-20AcCoA-2Dindependent-20flux-20through-20the-20bottom-20portion-20of-20the-20TCA-20cycle-20while-20accumulating-20pyruvate-20and-20aspartate-20that-20rescue-20their-20redox-20defects.-0A-0A-3Csmall-3EPublished-20under-20license-20by-20The-20American-20Society-20for-20Biochemistry-20and-20Molecular-20Biology,-20Inc.-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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