The role of glutaminase filamentation on mitochondrial adaptation to amino acids deprivation

• Grant number: 24/17954-1
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: April 01, 2025
• End date: March 31, 2028
• Field of knowledge: Biological Sciences - Biochemistry - Metabolism and Bioenergetics
• Principal Investigator: Sandra Martha Gomes Dias
• Grantee: Vitor de Miranda Ramos
• Host Institution: Centro Nacional de Pesquisa em Energia e Materiais (CNPEM). Ministério da Ciência, Tecnologia e Inovação (Brasil). Campinas , SP, Brazil
• Associated research grant: 21/05726-6 - Metabolism in the microenvironment and the role of metabolic exchanges in tumor progression, AP.TEM

Abstract

When the availability of nutritional resources fails to meet cellular needs, cells activate adaptive responses to ensure their survival. The mitochondrion plays a crucial role in this process, adjusting its structure and function in response to environmental conditions. For example, the mitochondrial network can elongate in response to amino acid deficiency, ensuring adequate oxidation of alternative energy sources and ATP production. For this adaptation to occur, specialized proteins must detect and signal amino acid levels to other cellular systems. Recently, it has been demonstrated that the mitochondrial enzyme glutaminase (GLS), essential in glutamine metabolism, responds to its deprivation by forming supra-tetrameric filaments in the mitochondrial matrix. These filaments are necessary for the elongation of the mitochondrial network, preventing mitochondrial degradation through autophagy (mitophagy). However, the molecular mechanisms connecting glutamine deprivation, mitochondrial morphology, and GLS filamentation are not yet fully understood. Furthermore, the impact of these filaments on other aspects of mitochondrial function necessary for the adaptive response has not been explored. Therefore, this project aims to investigate the role of glutaminase filamentation in the mitochondrial response to amino acid deprivation. Specifically, we seek to understand which signaling pathways promote GLS filamentation in mitochondria, how this process interacts with mitochondrial dynamics proteins, and its effect on organelle physiology. Our goal is to contribute to the understanding of the regulatory mechanisms of mitochondrial morphology and function, which are essential for cellular survival, as well as to deepen the knowledge of glutaminase enzyme functions in cells.