Program:
CanCell “Young Shot” talk will be given by project group leader Maja Radulovic.
Meet the speaker - Light refreshments will be served after the talk at the canteen.
Atherosclerosis is a progressive insidious chronic disease that underlies most cardiovascular diseases (CVD), the main cause of death and disability in the world. The exact molecular and cellular factors that influence the initiation and progression of atherosclerotic lesions are extremely complex and poorly understood. However, it is known that LDL oxidation and lysosome dysfunction are key events in atherosclerosis. Recently, our group identified a novel family of oxidized lipids, cholesteryl hemiesters (ChE), by shotgun lipidomics in plasma of CVD patients. ChE are formed during LDL oxidation, in the arterial intima, and due to their amphiphilic properties, they are, with time, detected in plasma. The most prevalent ChE, cholesteryl hemiazelate, (ChA), is sufficient to cause lysosome dysfunction in macrophages and vascular smooth muscle cells (VSMC). ChE reach lysosomes by endocytosis and passive diffusion and once in lysosomes inhibit cargo degradation and egress, culminating with lysosomal lipid accumulation and acquisition of a foam cell-like phenotype. These outcomes can be attributed to the effects of ChE on biophysical properties of lysosomal membranes, causing changes in the v-ATPase activity, luminal pH changes and acidic hydrolase activity inhibition. Importantly, lysosome dysfunction has consequences for inter-organelle communication. Our recent data indicates that cholesteryl hemiglutarate (ChG), the second most abundant ChE in CVD patients, besides causing lysosome dysfunction also changes iron metabolism reducing the levels of the mitochondrial OXPHOS complexes. We are now looking at the existence of membrane contact sites between dysfunctional lysosomes and mitochondria and at their role in iron metabolism.