Role of Mfn2 and LRRK2 on endoplasmic reticulum-mitochondrial tethering

• Grant number: 17/11143-8
• Support type: Scholarships abroad - Research Internship - Master's degree
• Effective date (Start): October 23, 2017
• Effective date (End): April 22, 2018
• Field of knowledge: Biological Sciences - Genetics
• Principal Investigator: Marcos Roberto Chiaratti
• Grantee: Bruna Martins Garcia
• Supervisor abroad: Luca Scorrano
• Home Institution: Centro de Ciências Biológicas e da Saúde (CCBS). Universidade Federal de São Carlos (UFSCAR). São Carlos , SP, Brazil
• Local de pesquisa : Fondazione Ricerca Biomedica Avanzata, Italy
• Associated to the scholarship: 16/11935-9 - Effect of the knockout of Mitofusin 2 on mitochondria, endoplasmic reticulum and mitophagy in murine oocytes, BP.MS

Abstract

The endoplasmic reticulum (ER) is a dynamic organelle responsible for the synthesis, modification, folding and transport of secretory and membrane proteins, as well as a storage of Ca2+ and lipid biosynthesis. In addition, the ER has contact sites with the outer mitochondrial membrane (mitochondrial-associated membranes, MAM), which is of great importance for regulation of lipid metabolism and Ca2+ signaling. Thus, MAM influences energetic metabolism, cellular proliferation, autophagy and apoptosis; also, alterations in MAM may result in several metabolic (i.e., obesity and diabetes) and neurodegenerative (i.e., Alzheimer and Parkinson) syndromes. Although several studies are emerging involving the functional characterization of MAM, some questions remain unclear concerning how intracellular signals promote MAM formation, which proteins are involved in ER-mitochondrial contact sites, and how MAM may impact on cell homeostasis. Mitofusin 2 (Mfn2) was the first protein characterized to be involved with MAM formation. Recently, we found that the conditional ablation of Mfn2 subtle affects oocyte development, leading to altered glucose metabolism in the progeny. On the other hand, preliminary data linked Leucine Repeats Rich Kinase 2 (LRRK2) and MAM, with possible implications to development of Parkinson's disease (PD). Hence, we intend with this work to address the role of Mfn2 and LRRK2 on ER-mitochondrial tethering. Specifically, we will evaluate i) the ER and mitochondria morphology and tethering between these organelles in mouse oocytes lacking Mfn2; ii) whether LRRK2 is at the ER-mitochondrial interfacein murine embryonic fibroblasts (MEFs); and, iii) whether PD LRRK2 mutants alter ER-mitochondrial tethering and communication. We expect with these experiments to provide new evidences linking Mfn2 and LRRK2 with development of metabolic and neurodegenerative diseases, respectively. (AU)