Unraveling the working mechanism of a tumor suppressor lipid

• Applicant: Professor Dr. Joost Holthuis
• Subject Area: Biochemistry ; Cell Biology
• Term: since 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 378148610

Ceramides attract wide attention as tumor suppressor lipids that can act directly on mitochondria to trigger Bax-mediated cell death. While ceramide engagement in mitochondrial apoptosis is clinically relevant, molecular details of the underlying mechanism are largely unknown. A chemical screen for ceramide binding proteins combined with computer simulations and functional studies in cancer cells previously led us to identify the voltage-dependent anion channel VDAC2 as critical effector of ceramide-mediated apoptosis. VDAC residues involved in ceramide binding are also required for mobilizing hexokinase type-I to mitochondria, a potential checkpoint in apoptosis. Collectively, our data support a model in which ceramides function as modulators of VDAC-based platforms to control mitochondrial recruitment of pro- and anti-apoptotic machinery. The central aim of the current project is to challenge fundamental aspects of this model by exploiting switchable ceramide transfer proteins and mitochondrial-specific release of photocaged ceramides in combination with live cell imaging and functional studies. Understanding the molecular principles by which ceramides commit cells to death may facilitate the development of novel strategies to enhance their anti-tumor potential for therapeutic treatment.

• DFG Programme: Research Grants