RESUMO
Mitochondrial electron transport drives ATP synthesis but also generates reactive oxygen species, which are both cellular signals and damaging oxidants. Superoxide production by respiratory complex III is implicated in diverse signaling events and pathologies, but its role remains controversial. Using high-throughput screening, we identified compounds that selectively eliminate superoxide production by complex III without altering oxidative phosphorylation; they modulate retrograde signaling including cellular responses to hypoxic and oxidative stress.
Assuntos
Complexo III da Cadeia de Transporte de Elétrons/metabolismo , Sequestradores de Radicais Livres/farmacologia , Mitocôndrias/efeitos dos fármacos , Pirazóis/farmacologia , Pirimidinas/farmacologia , Superóxidos/antagonistas & inibidores , Trifosfato de Adenosina/biossíntese , Animais , Antimicina A/análogos & derivados , Antimicina A/antagonistas & inibidores , Antimicina A/farmacologia , Relação Dose-Resposta a Droga , Feminino , Células HEK293 , Ensaios de Triagem em Larga Escala , Humanos , Peróxido de Hidrogênio/antagonistas & inibidores , Peróxido de Hidrogênio/metabolismo , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Masculino , Mitocôndrias/metabolismo , Fosforilação Oxidativa/efeitos dos fármacos , Estresse Oxidativo , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Transdução de Sinais , Superóxidos/metabolismoRESUMO
The identification of factors that promote ß cell proliferation could ultimately move type 1 diabetes treatment away from insulin injection therapy and toward a cure. We have performed high-throughput, cell-based screens using rodent ß cell lines to identify molecules that induce proliferation of ß cells. Herein we report the discovery and characterization of WS6, a novel small molecule that promotes ß cell proliferation in rodent and human primary islets. In the RIP-DTA mouse model of ß cell ablation, WS6 normalized blood glucose and induced concomitant increases in ß cell proliferation and ß cell number. Affinity pulldown and kinase profiling studies implicate Erb3 binding protein-1 and the IκB kinase pathway in the mechanism of action of WS6.