Conserved Mediator subunit MDT‐15 assures metabolic homeostasis

Abstract

Metabolic regulation occurs to a significant extent at the level of gene expression. We study the Mediator complex, a conserved multiprotein transcriptional coregulator. Interestingly, several Mediator subunits regulate lipid biology. We previously showed that the Caenorhabditis elegans Mediator subunit MDT‐15 is required for normal fatty acid distribution and for ingestion‐associated stress responses. Here, we show that loss of mdt‐15 leads to increased ER stress, as shown by upregulation of HSP‐4/BiP and of spliced XBP‐1 mRNA. We observed similar changes in worms with depleted fat‐6/Stearoyl‐CoA desaturase, suggesting that lack of monounsaturated fatty acids causes ER stress. However, although dietary complementation with oleic acid rescued ER stress in fat‐6 worms, it only partially rescued the ER stress in mdt‐15 animals, suggesting that additional defects cause excess ER stress. Interestingly, we find that mdt‐15 is also required for oxidative stress responses, suggesting that disturbed redox balance contributes to ER stress in mdt‐15 worms. Our data provide evidence for broad cytoprotective actions of MDT‐15, which maintains normal lipid profiles and assures a favorable redox environment.