Abstract
1178-P: MSDC-0602 Directly Inhibits Mitochondrial Pyruvate Transport
Diabetes (New York, N.Y.), Vol.68(Supplement_1)
06/01/2019
DOI: 10.2337/db19-1178-P
Abstract
The mitochondrial pyruvate carrier (MPC) occupies a carbohydrate metabolism nexus and is a potential target of thiazolidinediones (TZDs) prescribed to treat the metabolic syndrome. MSDC-0602, a TZD-like, PPARγ sparing molecule, is currently in phase 2B clinical for NASH treatment following positive results in animal studies. Previous research demonstrates that MSDC-0602 inhibits mitochondrial pyruvate oxidation and physically interacts with the MPC. However, the extent to which MSDC-0602 directly inhibits mitochondrial pyruvate uptake has not been fully resolved. Here, we aimed to comprehensively test the action of MSDC-0206 as a specific MPC inhibitor. We examined MSDC-0602 treatment effects on pyruvate oxidation and pyruvate transport by isolated liver mitochondria from normal chow (NCD)- and high fat diet (HFD)-fed mice. MSDC-0602 inhibited pyruvate-driven State III and State IV+Uncoupled respiration in a dose dependent manner. MSDC-0602 reduced pyruvate-driven respiration to levels observed for liver mitochondria isolated from MPC liver knockout (MPC LivKO) mice. NCD and HFD mice showed similar response to MSDC-0602. These data confirm that MSDC-0602 inhibits pyruvate-driven respiration. However, pyruvate oxidation is an indirect measure of MPC activity because it depends upon pyruvate-oxidizing enzymes and electron transport. To directly test the action of MSDC-0602 on mitochondrial pyruvate transport, we performed isolated mitochondria 14C-pyruvate uptake assays. Pyruvate uptake was significantly decreased by MSDC-0602 to rates observed for MPC LivKO mouse liver mitochondria. Finally, we examined effects of MSDC-0602 metabolites and found them to also inhibit isolated liver mitochondria pyruvate oxidation. Together, these data demonstrate that MSDC-0602 directly and specifically inhibits MPC activity as a mechanism for impairing downstream pyruvate utilization. The therapeutic effects of MSDC-0602 may be conferred by MPC inhibition and resulting metabolic adaptations.
Disclosure
A.J. Rauckhorst: None. L. Oonthonpan: None. E.B. Taylor: Research Support; Self; Cirius Therapeutics.
Funding
American Diabetes Association (1-18-PDF-060 to A.J.R.); National Institutes of Health (DK104998); Cirius Therapeutics
Details
- Title: Subtitle
- 1178-P: MSDC-0602 Directly Inhibits Mitochondrial Pyruvate Transport
- Creators
- ADAM J. Rauckhorst - Iowa City, IALALITA Oonthonpan - Iowa City, IAERIC B. Taylor - Iowa City, IA
- Resource Type
- Abstract
- Publication Details
- Diabetes (New York, N.Y.), Vol.68(Supplement_1)
- DOI
- 10.2337/db19-1178-P
- ISSN
- 0012-1797
- eISSN
- 1939-327X
- Language
- English
- Date published
- 06/01/2019
- Academic Unit
- Molecular Physiology and Biophysics; Fraternal Order of Eagles Diabetes Research Center
- Record Identifier
- 9984384333002771
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