Secretariat, Alumni Association, IDAC |
Date | Wednesday,24 September 2025, 10:00~ |
Room | 7th Floor, Seminar Room 1, IDAC Center for Basic Aging Research |
Title | Identification of Druggable and Redox Vulnerabilities in Cancer |
Speaker | Dr. Liron Bar-peled |
Affiliation | The Center for Cancer Research at Massachusetts General Hospital,The Department of Medicine at Harvard Medical School |
Organizer | Shinpei Kawaoka (Dept. Integrative Bioanalytics, ext.8568) |
Abstract | Reactive oxygen species (ROS) underlie human pathologies including cancer and neurodegeneration. However, the proteins which sense ROS levels and regulate their production through their cysteines remain ill defined. Systematic base-editor and computational screens revealed cysteines in VPS35–a Retromer trafficking complex member, when mutated phenocopy inhibition of mitochondrial translation. We find that VPS35 underlies a reactive metabolite-sensing pathway that lowers mitochondrial translation to decrease ROS levels. Intracellular H2O2 oxidizes cysteines within VPS35, resulting in Retromer dissociation from endosomal membranes and subsequent plasma membrane remodeling. We demonstrate that plasma membrane localization of Retromer substrate SLC7A1 is required to sustain mitochondrial translation. Furthermore, lowering VPS35 levels or oxidation of its ROS-sensing cysteines confers resistance to ROS-generating chemotherapies including cisplatin in ovarian cancer models. Thus, we identify that intracellular ROS levels are communicated to the plasma membrane through VPS35 to regulate mitochondrial translation, connecting cytosolic ROS sensing to mitochondrial ROS production. |