Scholarship 24/00748-0 - Calcificação vascular, Metabolismo - BV FAPESP
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Mitochondrial calcium transport and the control of bone and vascular mineralization

Grant number: 24/00748-0
Support Opportunities:Scholarships in Brazil - Post-Doctoral
Start date until: September 01, 2024
End date until: August 31, 2026
Field of knowledge:Biological Sciences - Biochemistry - Metabolism and Bioenergetics
Principal Investigator:Alicia Juliana Kowaltowski
Grantee:Marcos Antonio Eufrásio Cruz
Host Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

The transport of calcium in and out of the mitochondrial matrix has critical effects on cellular energy metabolism, signaling, and survival. Briefly, calcium influx into the mitochondrial matrix is controlled by the mitochondrial calcium uniporter (MCU) and calcium efflux by the sodium/calcium exchanger (NCLX). The ability of mitochondria to concentrate large amounts of calcium in a controlled manner has long been implicated in osteogenesis, the process in which our bones are formed. For bone formation, osteoblasts deposit an extracellular matrix (ECM) rich in type I collagen, that is further mineralized with hydroxyapatite crystals. Interestingly, in the pathology of vascular calcification, cells under stress switch to an osteoblast-like phenotype and undergo mineralization of their ECM. Surprisingly, the influence of mitochondrial calcium transporters in osteogenesis was never explored at a molecular level. In this project, we propose to uncover how transport of calcium in and out of the mitochondrial matrix is linked to the formation of a mineralized ECM, both in health and disease. Using in vitro osteoblast and vascular smooth muscle cell cultures, we will determine how mitochondrial parameters related to calcium homeostasis (morphology, calcium retention capacity and metabolic fluxes) are temporally regulated during osteogenesis. We will also explore the role of MCU and NCLX activities, using pharmacological inhibition and genetic knockdown, in the formation of a mineralized ECM. The knowledge produced from this project may uncover new mechanisms involved in the regulation of physiological and pathological calcification.

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