Research Seminar Speaker Series – Ambre Bertholet, UCLA – “Redefining the Mechanism of Action of Chemical Uncouplers for a New Generation of Antiobesogenic Drugs”

Please join us for our Research Seminar Series Speaker, Ambre Bertholet, Assistant Professor of Physiology, UCLA on: 

Mitochondria generate heat due to H+ leak (IH) across their inner membrane. IH results from the action of long-chain fatty acids (FA) on uncoupling protein 1 (UCP1) in brown fat and ADP/ATP carrier (AAC) in other tissues, but the underlying mechanism is poorly understood. Because no pharmacological activators of IH via UCP1 and AAC are known, IH is induced by protonophores such as 2,4-dinitrophenol (DNP) and cyanide-4-(trifluoromethoxy) phenylhydrazone (FCCP) that are thought to increase IH independently of membrane proteins. Protonophores are highly effective in combating obesity, insulin resistance, type II diabetes, and fatty liver in animal models, but because they indiscriminately increase H+ conductance across all biological membranes and have adverse side effects, their use in humans is restricted. Here we report the first direct measurement of IH induced by common protonophores and discover that their mechanism of action in mitochondria was significantly misunderstood. IH induced by DNP and other protonophores depends on AAC and UCP1. Thus, common protonophoric uncouplers emerge as the first synthetic activators of IH via UCP1 and AAC identified to date, paving the way for the development of new and more specific activators of these two proteins. 

Friday:  February 24, 2023

Time:  12:00 – 1:00 p.m.

Location:  121 Bldg. – 1111 classroom & Via Zoom (See Outlook invite for Zoom Link)