Investigation of mitochondrial calcium transport on the modulation of mTORC1 activity mediated by amino acids

• Grant number: 24/07643-9
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: July 01, 2024
• End date: December 31, 2024
• Field of knowledge: Biological Sciences - Biochemistry - Metabolism and Bioenergetics
• Principal Investigator: Alicia Juliana Kowaltowski
• Grantee: Marcos Vinícius Caetano
• Host Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 20/06970-5 - Mitochondrial ion transporters as sensors and regulators in energy metabolism, AP.TEM

Abstract

The ability to sense the environment and generate appropriate responses are fundamental features for the survival of living organisms. An important signaling hub and a key controller of cellular metabolism, is the mechanistic target of rapamycin (mTOR). mTOR complex 1 (mTORC1) is primarily involved in cell growth and the availability of amino acids is one of the main stimuli for its activation. Along with mTORC1, mitochondrial metabolism is also central in nutrient sensing and coordination of adaptive cellular responses. Given the well-established role of mitochondria in the modulation and regulation of intracellular calcium signaling, as well as the participation of calcium in the regulation of mTORC1, it is rational to speculate that calcium may have an important role in the communication between mitochondria and mTORC1. In fact, previous data from our group demonstrated that pharmacological inhibition of mitochondrial calcium efflux through the mitochondrial Na+/Li+/Ca2+ exchanger (NCLX) promotes an increase in mTORC1 activity in response to recovery from amino acid and serum deprivation. Thus, this project aims to identify which amino acids mediate this differential activity and through which signaling pathway, as well as investigate whether NCLX inhibition affects mitochondrial metabolism in the presence or absence of specific amino acids. The working plan for this project will consist of cell culture experiments with nutrient starvation followed by a refeeding with specific amino acids, in addition to in vitro metabolic analysis, both in the presence or absence of pharmacological inhibition of NCLX. Therefore, this project aims to elucidate a new mechanism on how Ca2+ transport across the inner mitochondrial membrane regulates cellular metabolism.