Crosstalk Between Lipid Droplets and Other Organelles in Podocytes

University Of Miami School Of Medicine, Coral Gables FL

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Abstract

Research supports a role for reduced cholesterol efflux and lipid droplet (LD) accumulation in mitochondrial dysfunction (MD) and podocyte injury in the pathogenesis of glomerular diseases of metabolic and non-metabolic origin, including Alport Syndrome (AS). Less is known about the contribution of triglyceride (TG) accumulation in LDs to MD and podocyte injury. LDs regulate the storage and homeostasis of intracellular TGs and regulate the availability of free fatty acids (FFAs), which can be oxidized in mitochondria and used as an energy source. Proper contact of LDs with mitochondria is mediated by LD-associated proteins, such as perilipin 5 (PLIN5), and is instrumental for FA synthesis and breakdown. PLIN5 is a protein that regulates TG metabolic pathways and cellular energy homeostasis through its role in the lipolysis of TGs stored in LDs, mediates LD-mitochondrial contact formation, and serves as a substrate for chaperone-mediated autophagy (CMA). However, little is known about the function of PLIN5 in podocytes. In preliminary data, we demonstrate decreased PLIN5 expression in glomeruli of patients with AS, in kidneys of Col4a3 KO (AS mice) and AS podocytes, and in a zebrafish model of AS when compared to controls. In AS podocytes, PLIN5 deficiency is associated with increased lipolysis, FFA accumulation, and reduced LD- mitochondrial contact formation and mitochondrial membrane potential, which was restored by PLIN5 overexpression. AS podocytes have an increased autophagosome number compared to WT, often in proximity of mitochondria, suggesting increased mitophagy. PLIN5 expression is restored by Ezetimibe (EZ), a compound that we found to partially protect AS mice from the development of proteinuria. Our results suggest an important role for PLIN5 deficiency in lipotoxicity-induced MD and podocyte injury and renal disease progression in AS. The overall goal of this proposal is to investigate a novel mechanism linking PLIN5 deficiency to lipotoxicity- mediated MD, CMA and podocyte injury in AS. We hypothesize that PLIN5 deficiency in AS causes TG-rich LD accumulation due to impaired CMA, FFA accumulation due to increased TG lipolysis and impaired LD-mitochondrial contact formation, resulting in lipotoxicity-induced mitochondrial dysfunction. We propose a combined in vitro and in vivo approach to investigate the mechanism by which PLIN5 deficiency causes lipotoxicity-induced MD and podocyte injury (aim 1), and in renal failure (aim 2) in AS. If successful, this innovative study will link PLIN5 deficiency to a novel pathway of lipotoxicity-induced MD and podocyte injury and may lead to the identification of new drug targets for the treatment of patients with proteinuric kidney diseases associated with altered GBM, such as AS.