Hodges 2021 J Biol Chem

From Bioblast
Publications in the MiPMap
Hodges WT, Jarasvaraparn C, Ferguson D, Griffett K, Gill LE, Chen Y, Ilagan MXG, Hegazy L, Elgendy B, Cho K, Patti GJ, McCommis KS, Finck BN (2021) Mitochondrial pyruvate carrier inhibitors improve metabolic parameters in diet-induced obese mice. J Biol Chem 298:101554.

Β» PMID: 34973337 Open Access

Hodges Wesley T, Jarasvaraparn Chaowapong, Ferguson Daniel, Griffett Kristine, Gill Lauren E, Chen Yana, Ilagan Ma Xenia G, Hegazy Lamees, Elgendy Bahaa, Cho Kevin, Patti Gary J, McCommis Kyle S, Finck Brian N (2021) J Biol Chem

Abstract: The mitochondrial pyruvate carrier (MPC) is an inner mitochondrial membrane complex that plays a critical role in intermediary metabolism. Inhibition of the MPC, especially in liver, may have efficacy for treating type 2 diabetes mellitus. Herein, we examined the anti-diabetic effects of zaprinast and 7ACC2, small molecules which have been previously reported to act as MPC inhibitors. Both compounds activated a bioluminescence resonance energy transfer (BRET)-based MPC reporter assay (reporter sensitive to pyruvate; RESPYR) and potently inhibited pyruvate-mediated respiration in isolated mitochondria. Furthermore, zaprinast and 7ACC2 acutely improved glucose tolerance in diet-induced obese mice in vivo. Although some findings were suggestive of improved insulin sensitivity, hyperinsulinemic-euglycemic clamp studies did not detect enhanced insulin action in response to 7ACC2 treatment. Rather, our data suggest acute glucose-lowering effects of MPC inhibition may be due to suppressed hepatic gluconeogenesis. Finally, we used RESPYR to screen a chemical library (Pharmakon 1600) of drugs and identified 35 potentially novel MPC modulators. Using available evidence, we generated a pharmacophore model to prioritize which hits to pursue. Our analysis revealed carsalam and six quinolone antibiotics, as well as 7ACC1, share a common pharmacophore with 7ACC2. We validated that these compounds are novel inhibitors of the MPC and suppress hepatocyte glucose production, and demonstrated that one quinolone (nalidixic acid) improved glucose tolerance in obese mice. In conclusion, these data demonstrate the feasibility of therapeutic targeting of the MPC for treating diabetes and provide scaffolds that can be used to develop potent and novel classes of MPC inhibitors.

β€’ Bioblast editor: Plangger M β€’ O2k-Network Lab: US MO St Louis McCommis KS, US MO St Louis Finck B


Labels: MiParea: Respiration 


Organism: Mouse  Tissue;cell: Heart  Preparation: Isolated mitochondria 


Coupling state: OXPHOS  Pathway: N, NS  HRR: Oxygraph-2k 

2022-01 

Cookies help us deliver our services. By using our services, you agree to our use of cookies.