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Property "Has-20abstract" (as page type) with input value "Mitochondria-20are-20emerging-20as-20intriguing-20targets-20for-20anti-2Dcancer-20agents.-20We-20tested-20the-20anti-2Dneoplastic-20activity-20of-20a-20mitochondrially-20targeted-20analog-20of-20alpha-2Dtocopheryl-20succinate-20(MitoVES),-20a-20compound-20with-20high-20propensity-20to-20induce-20apoptosis-20in-20cancer-20cells-20by-20targeting-20complex-20II-20(CII)-20of-20mitochondrial-20respiratory-20chain.-20The-20parental-20compound,-20alpha-2Dtocopheryl-20succinate-20(α-2DTOS),-20displays-20anti-2Dcancer-20properties,-20and-20we-20reasoned-20to-20modified-20VES-20by-20tagging-20the-20triphenylphosphonium-20group-20to-20its-20structure-20to-20enhance-20these-20effects-20via-20mitochondrial-20destabilization.-20A-20major-20mechanism-20how-20these-20compounds-20cause-20apoptosis-20in-20cancer-20cells-20is-20generation-20of-20reactive-20oxygen-20species-20(ROS),-20most-20likely-20the-20outcome-20of-20CII-20-20inhibition-20after-20-0Aα-2DTOS-2FMitoVES-20binding-20to-20the-20proximal-20UbQ-2D-20binding-20site-20(Qp)-20of-20the-20SDHC-20subunit-20of-20CII-20(1,2).-20-0AThe-20effect-20of-20small-20anti-2Dcancer-20compounds-20on-20mitochondria-20can-20involve-20suppression-20of-20their-20respiration-20(3).-20We-20tested-20this-20for-20α-2DTOS-20and-20MitoVES-20in-20malignant-20mesothelioma-20(MM)-20cells,-20first-20assessing-20the-20effect-20of-20the-20two-20agents-20on-20routine-0Arespiration,-20i.e.-20total-20oxygen-20consumption-20by-20whole-20cells-20in-20the-20cultivation-20medium-20in-20the-20absence-20of-20an-20uncoupler.-20MitoVES-20was-20much-20higher-20efficient-20in-20inhibition-20of-20respiration-20than-20α-2DTOS,-20which-20was-20relatively-20inefficient.-20Interestingly,-20MitoVES-20acts-20as-20an-20uncoupler-20at-20low-20concentrations-20(1–2-20μM).-20We-20next-20tested-20the-20effect-20of-20MitoVES-20and-20α-2DTOS-20on-20the-20contribution-20of-20CI-20and-20CII-20to-20mitochondrial-20respiration-20in-20permeabilized-20cells.-20MM-20cells-20respire-20predominantly-20via-20CII-20and-20reveals-20a-20superior-20effect-20of-20MitoVES,-20which-20at-20lower-20concentrations-20uncoupled-20CII-2Ddependent-20respiration-20in-20several-20of-20the-20cell-20lines,-20followed-20by-20its-20inhibition.-20The-20agent-20also-20exerted-20an-20effect-20on-20CI-20at-20higher-20concentrations.-0AIn-20the-20next-20experiments,-20we-20tested-20the-20effect-20of-20the-20VE-20analogues-20on-20the-20assembly-20of-20mitochondrial-20(super)complexes.-20While-20the-20assembly-20of-20CII,-20the-20most-20sensitive-20MitoVES-20target,-20was-20not-20affected,-20the-20agent-20destabilized-20the-20higher-20forms-20of-20supercomplexes,-20referred-20to-20as-20respirasomes.-20α-2DTOS-20was-20much-20less-20efficient.-20Further,-20we-20found-20that-20MitoVES-20suppressed-20CII-20and-20CI-20activity-20using-20the-20in-2Dgel-20assay-20following-20the-20separation-20of-20the-20mitochondrial-20fraction-20by-20clear-20native-20electrophoresis.-20These-20effects-20on-20electron-20transport-20and-20oxidative-20phosphorylation-20may-20be-20explained-20by-20the-20interaction-20of-20MitoVES-20with-20CII,-20which-20results-20in-20ROS-20generation-20and-20subsequent-20effect-20on-20mitochondrial-20(super)complexes,-20although-20the-20exact-20mechanism-20is-20yet-20to-20be-20established.-20-0AWe-20propose-20that-20mitochondrial-20targeting-20of-20VES-20maximises-20its-20anti-2Dcancer-20efficacy,-20endowing-20it-20with-20a-20substantial-20translational-20relevance." contains invalid characters or is incomplete and therefore can cause unexpected results during a query or annotation process.

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