Characterizing the contribution of chaperone-mediated autophagy to endoplasmic reticulum and lipid droplet homeostasis.

• Applicant: Dr. Philipp Kirchner
• Subject Area: Cell Biology
• Term: from 2015 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 272981538

Cellular and organ deterioration in old organisms results, at least in part, from a failure of the systems responsible for the maintenance of cellular quality control. Malfunctioning of these surveillance systems also underlies the basis of severe diseases associated with aging such as neurodegeneration, metabolic disorders or muscle weakness. Chaperone-mediated autophagy (CMA) is a catabolic pathway for the degradation of selective cytosolic proteins in lysosomes that contributes to cellular quality control and maintenance of the cellular energetic balance. Importantly, CMA activity decreases with age and restoring normal CMA activity in aged rodents improves cellular homeostasis and preserves organ function. Recently, cells with compromised CMA were found to be more sensitive to endoplasmic reticulum (ER) stress and to challenge with dietary lipids. In both the ER and on lipid storage organelles, so-called lipid droplets, specific proteins were identified that can be substrates for CMA-mediated degradation. The aim of the proposed project is to investigate if changes in the regulated degradation of these proteins by CMA modulate ER homeostasis and lipid droplet turnover. Therefore, I will determine the reaction of cellular models, expressing CMA-resistant variants of the ER or lipid droplet proteins, to ER stressors and lipogenic challenges. This will help to understand the role of CMA in the maintenance of ER homeostasis and mobilization of lipid droplets. Furthermore, because the ER and lipid droplets share both physical and functional connections these results can also be utilized to characterize the possible interplay between the effects of CMA on these organelles. Understanding the impact of compromised CMA on individual cellular processes is important to elucidate how functional decline of CMA contributes to aging and aging-associated disorders.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professorin Ana Maria Cuervo, Ph.D.