The 2-oxoglutarate carrier promotes liver cancer by sustaining mitochondrial GSH despite cholesterol loading

Publication date: April 2018 Source:Redox Biology, Volume 14 Author(s): Anna Baulies, Joan Montero, Nuria Matías, Naroa Insausti, Oihana Terrones, Gorka Basañez, Carmen Vallejo, Laura Conde de La Rosa, Laura Martinez, David Robles, Albert Morales, Joaquin Abian, Montserrat Carrascal, Keigo Machida, Dinesh B.U. Kumar, Hidekazu Tsukamoto, Neil Kaplowitz, Carmen Garcia-Ruiz, José C. Fernández-Checa Cancer cells exhibit mitochondrial cholesterol (mt-cholesterol) accumulation, which contributes to cell death resistance by antagonizing mitochondrial outer membrane (MOM) permeabilization. Hepatocellular mt-cholesterol loading, however, promotes steatohepatitis, an advanced stage of chronic liver disease that precedes hepatocellular carcinoma (HCC), by depleting mitochondrial GSH (mGSH) due to a cholesterol-mediated impairment in mGSH transport. Whether and how HCC cells overcome the restriction of mGSH transport imposed by mt-cholesterol loading to support mGSH uptake remains unknown. Although the transport of mGSH is not fully understood, SLC25A10 (dicarboxylate carrier, DIC) and SLC25A11 (2-oxoglutarate carrier, OGC) have been involved in mGSH transport, and therefore we examined their expression and role in HCC. Unexpectedly, HCC cells and liver explants from patients with HCC exhibit divergent expression of these mitochondrial carriers, with selective OGC upregulation, which contributes to mGSH maintenance. OGC but not DIC downregulation by siRNA deplete...
Source: Redox Biology - Category: Biology Source Type: research