A @entity6217 -Mediated Transcriptional Network Maintains Mitochondrial Redox and Bioenergetic Homeostasis against @entity632 -Induced @entity137 in XXXX Cardiomyocytes: Implementation of TT21C.

@entity632 @entity1 @entity137 @entity4723 @entity25577 @entity9859 @entity6217 @entity5912 @entity3105 @entity224 @entity855 @entity2383
UNASSIGNED: Chemical @entity137 testing is fast moving in a direction that relies increasingly on cell-based in vitro assays anchored on @entity137 pathways according to the @entity137 testing in the 21st century vision. Identifying points of departure (POD) via these assays and revealing their mechanistic underpinnings via computational modeling of the relevant pathways are critical and challenging steps. Here we used @entity632 ( @entity3105 ) as a prototype chemical to study @entity2383 in @entity1 AC16 cells. @entity2383 has been linked to cardiovascular risk of @entity3105 , which has limited its clinical use as an antitumor drug. Our in vitro study revealed a well-defined POD concentration of @entity3105 below which adaptive induction of proliferator-activated receptor-y coactivator-1a ( @entity6217 ) -mediated mitochondrial genes, including @entity25577 , @entity4723 , @entity5912 , and @entity9859 , concurred with negligible changes in mitochondrial @entity224 and @entity137 . At higher @entity3105 concentrations adversity became significant with elevated @entity224 and suppressed @entity855 levels. A computational model was formulated to simulate the @entity6217 -mediated transcriptional network comprising multiple negative feedback loops that underlie redox and bioenergetics homeostasis in the mitochondrion. The model recapitulated the transition phase from adaptive to adverse responses, supporting the notion that saturated induction of @entity6217 -mediated gene network underpins POD. The model further predicts (follow-up experiments verified) that silencing @entity6217 compromises the adaptive function of the transcriptional network, leading to disruption of mitochondria and @entity137 at lower @entity3105 concentrations. In summary, our study demonstrates that combining pathway-focused in vitro assays and computational simulation of relevant biochemical network is synergistic for understanding dose-response behaviors in the low-dose region and identifying POD.
