Thiazolidinedione (TZD) insulin sensitizers have the potential to effectively treat a number of human diseases, however the currently available agents have dose-limiting side effects that are mediated via activation of the transcription factor PPARγ. We have recently shown PPARγ-independent actions of TZD insulin sensitizers, but the molecular target of these molecules remained to be identified. Here we use a photo-catalyzable drug analog probe and mass spectrometry-based proteomics to identify a previously uncharacterized mitochondrial complex that specifically recognizes TZDs. These studies identify two well-conserved proteins previously known as brain protein 44 (BRP44) and BRP44 Like (BRP44L), which recently have been renamed Mpc2 and Mpc1 to signify their function as a mitochondrial pyruvate carrier complex. Knockdown of Mpc1 or Mpc2 in Drosophila melanogaster or pre-incubation with UK5099, an inhibitor of pyruvate transport, blocks the crosslinking of mitochondrial membranes by the TZD probe. Knockdown of these proteins in Drosophila also led to increased hemolymph glucose and blocked drug action. In isolated brown adipose tissue (BAT) cells, MSDC-0602, a PPARγ-sparing TZD, altered the incorporation of 13C-labeled carbon from glucose into acetyl CoA. These results identify Mpc1 and Mpc2 as components of the mitochondrial target of TZDs (mTOT) and suggest that understanding the modulation of this complex, which appears to regulate pyruvate entry into the mitochondria, may provide a viable target for insulin sensitizing pharmacology.
This paper presents distributed power quality conditioning system to compensate current and voltage distortions in three-phase four-wire networks caused by unbalanced non-linear single-phase loads. The proposed conditioning system consists of several hybrid filter units installed in various nodes for compensation of excessive neutral currents and voltage distortions in a selected area of the distribution network. The system is open and it can be easily modified by installation of new filter units. A novel hybrid filter design procedure based on filter frequency characteristics optimization in the parameters of passive and active parts is presented. A digital system of control signal computation for active filters based on the use of modern methods of spectral analysis is considered. The proposed digital control system enables selective compensation of fundamental and harmonic components. The mathematical model of the proposed power quality conditioning system is developed in the MatLab software. The simulated results show that the presented conditioning system reduces the level of neutral conductor currents and the voltage unbalance as well ensures harmonic compensation in three-phase four-wire networks.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.