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The role of MFN2 on metabolic repercussions during osteoclast differentiation

Grant number: 21/09880-0
Support type:Scholarships abroad - Research Internship - Doctorate
Effective date (Start): December 01, 2021
Effective date (End): November 30, 2022
Field of knowledge:Biological Sciences - Immunology - Cellular Immunology
Principal researcher:Sandra Yasuyo Fukada Alves
Grantee:Lucas Gabriel Rodrigues Venturini
Supervisor abroad: Luke Anthony John O'Neill
Home Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Research place: Trinity College Dublin, Ireland  
Associated to the scholarship:18/17167-9 - Role of mitofusin 2 and mitochondrial dynamics on osteoclasts bone resportion in an Osteoarthritis experimental model, BP.DR

Abstract

Osteoclasts are giant, multinucleated cells and the only cell in human organism with the bone resorption function. To perform this function, a series of morphological and biochemical adaptations that require a large amount of energy are necessary, which makes these cells rich in mitochondria, with an increase in mitochondrial mass during osteoclast differentiation and a high energy production via oxidative phosphorylation. For these reasons, we hypothesized that mitofusin 2 (MFN2), a molecule involved in mitochondrial fusion and biogenesis, would be increased during osteoclast differentiation. Using RT-qPCR we observed an increase in MFN2 expression during murine osteoclast differentiation. To assess the role of MFN2 in osteoclast differentiation, MFN2 was conditionally knocked out in mouse myeloid precursors and were stimulated with M-CSF and RANKL to generate osteoclasts. We observed that the MFN2 deletion led to impairment of both osteoclast differentiation and function. In vivo, the conditional knockout of MFN2 in osteoclasts prevented ovariectomy-induced bone loss in mice, which mimics osteoporosis in humans. Regarding the mechanism underlying MFN2 regulating osteoclasts differentiation and function , we observed that the deletion of MFN2 in osteoclasts induced an impairment of energy production via oxidative phosphorylation . To further investigate the role of MFN2 on metabolism of osteoclast during its differentiation, this project aims to evaluate the effect of MFN2 deletion on osteoclast's metabolic changes by metabolomics We also plan to evaluate the ability of MFN2 to bind and inhibit PKM2 and check if this interaction would affect osteoclastogenesis. Lastly, we plan to evalute the effect of MFN2 deletion on mitophagy and mitochondrial biogenesis.

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