Novel Role of Bscl2 in Cardiac Substrate Metabolism and Function

Project Summary Metabolic perturbations underpin a wide variety of cardiomyopathies. Currently, there are no specific treatments for preventing the onset or progression of cardiomyopathies to heart failure, one of the leading causes of death and disability worldwide. BSCL2/Seipin is a highly conserved endoplasmic reticulum (ER) protein widely implicated in lipid droplet biogenesis and triglyceride (TG) metabolism. However, the molecular machinery responsible for BSCL2-regulated cardiac lipid metabolism has not been elucidated. This grant addresses novel linkages between BSCL2, TG lipolysis, and mitochondrial function in the heart. We found that cardiac BSCL2 deletion elevates adipose triglyceride lipase (ATGL) expression and fatty acid (FA) oxidation, and causes TG reduction and mild cardiac dysfunction with age. However, BSCL2 deletion completely rescues lethal metabolic cardiomyopathy in ATGL-deficient mice. This was achieved by restoring cardiac TG lipolysis and FA oxidation, suggesting the presence of other non-ATGL TG lipase (s)/players downstream of BSCL2. We further employed Bscl2 knock-in mouse and proteomics and showed that BSCL2 interacts with mitochondrial protein and co- fractionates with proteins present in ER membranes associated with mitochondria (MAM). We, therefore, hypothesize that BSCL2 mediates ATGL-independent TG catabolism, ER-mitochondria coupling, and mitochondrial function thus cardiac homeostasis and lipotoxic cardiomyopathy. Aim 1 will elucidate the importance and mechanisms of a novel TG lipase in the heart that controls cardiac triglyceride hydrolysis and FA oxidation downstream of BSCL2. Aim 2 will define whether BSCL2 interacts with a specific mitochondrial protein at ER/mitochondria contact sites to mediate mitochondrial function and lipotoxic cardiomyopathy. This study is highly significant as it defines the novel components and molecular machinery of BSCL2-mediated ATGL-independent pathways that regulate cardiac TG metabolism, MAM, mitochondrial metabolism, and heart function, which can potentially lay an intellectual groundwork for novel therapeutic approaches to metabolic cardiomyopathy.