Defining the mitochondrial function of acylglycerol kinase (AGK) associated with Sengers syndrome

• Applicant: Dr. Milena Vukotic
• Subject Area: Biochemistry
• Term: from 2014 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 251763979

AGK is a mitochondrial acylglycerol kinase that catalyzes phosphorylation of monoacylglycerol (MOG) and diacylglycerol (DAG) to lysophosphatidic acid (LPA) and phosphatidic acid (PA). Loss of function mutations in the Agk gene causes Sengers syndrome, a cardiomyopathy and skeletal myopathy. Some of the clinical symptoms of Sengers syndrome resemble Barth syndrome, which is caused by defects cardiolipin (CL) metabolism. CL is a mitochondria-specific phospholipid required for diverse mitochondrial processes. It is synthesized along an enzymatic cascade in the inner mitochondrial membrane from PA that is synthesized in the ER and transported to mitochondria. Because of similarities in clinical presentations between Sengers and Barth syndrome and the ability of AGK to produce PA in mitochondria, we hypothesize that PA synthesized by AGK represents a second source of PA for CL synthesis. Therefore we will employ genetic and biochemical approaches in mammalian cells to define the function of AGK in mitochondria. Moreover, we will define the AGK properties in modulation of cellular signaling pathways by its products, LPA and PA, which are potent bioactive phospholipids. These studies will broaden our knowledge on the function of AGK and help us to reveal the link between cardiolipin metabolism and Sengers syndrome.

• DFG Programme: Research Grants