Effects of mitochondrial calcium transport regulation on amino acid metabolism and urea cycle

• Grant number: 24/15581-3
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: February 01, 2025
• End date: January 31, 2030
• 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

In recent years, amino acid metabolism has been associated with various biological processes and with the pathogenesis of diseases. The urea cycle is a metabolic pathway responsible for converting ammonia excess, derived from the degradation of amino acids, into urea for excretion. To ensure the maintenance of homeostasis and nitrogen balance, the urea cycle enzymes expressions are modulated by several factors such as hormones and diet. The key enzyme that adjusts the flux through the urea cycle and is located in the mitochondrial matrix is carbamoyl phosphate synthetase I. This enzyme is allosterically activated by N-acetylglutamate, whose synthesis is stimulated by arginine and Ca2+. Mitochondria play a well-established role in metabolism and in regulating intracellular calcium, a process controlled by transporters in the inner mitochondrial membrane. Given the role of mitochondria in calcium homeostasis and the fact that urea cycle is modulated by Ca2+, this project aims to investigate the role of mitochondrial calcium transport, mediated by the mitochondrial calcium uniporter complex (MCU) and the mitochondrial Na+/Li+/Ca2+ exchanger (NCLX), in amino acid metabolism and the urea cycle under basal conditions and under different nutritional stimuli. Functional, molecular and metabolomics approaches will be used to achieve these objectives in different models: in vitro (gene knockdown and pharmacological inhibition) and in vivo (knockout mice). Thus, this project aims to uncover a new mechanism by which Ca2+ transport across the inner mitochondrial membrane regulates cellular metabolism.