Role of mitofusin 2 and mitochondrial dynamics in osteoclast differentiation and function

Author(s)

Lucas Gabriel Rodrigues Venturini

• Document type: Doctoral Thesis
• Press: Ribeirão Preto.
• Institution: Universidade de São Paulo (USP). Faculdade de Medicina de Ribeirão Preto (PCARP/BC)
• Defense date: 2023-10-25

Examining board members

Sandra Yasuyo Fukada Alves; Marcos Roberto Chiaratti; Julio Cesar Batista Ferreira; Luiz Osório Silveira Leiria

• Advisor: Sandra Yasuyo Fukada Alves

Abstract

Osteoclasts are tissue specific macrophages with the function of bone resorpt ion. Because they are giant and multinucleated cells, osteoclasts need, from their formation, through adhesion and movement on the bone surface and finally through the production of osteolytic enzymes, a high amount of energy. Mitochondria is the organelle responsible for energy production in animal cells and it is known that it has the ability to change its number, size and intracellular location through a process called mitochondrial dynamics, important for the differentiation of a lot of cells. Therefore , the aim of this work was to evaluate the role of mitochondrial dynamics in the differentiation of osteoclasts. To answer this objective, we first observed an increase in the area of mitochondria in differentiated osteoclasts when compared to mononuclear progenitors. We look for the expression of mitochondrial dynamics during osteoclast differentiation and saw an increase of mitochondrial fusion genes, in particular, mitofusin 2. We performed the conditional knockout of mitofusin 2 in osteoclast precursors and observed a decrease in the number of osteoclasts and area of bone resorption in knockout osteoclasts compared to the control in vitro. Going deeper into the effects of mitofusin 2 deletion in osteoclasts, we observed a reduction in the area of mitochondria, in the mitochondrial membrane potential, as well as in the production of energy via mitochondria in knockout group when compared to the control group, we also observed an increase in the production of lactate in knockout group. Finally, to observe the effect of mitofusin 2 deletion in an in vivo osteolytic model, we performed a conditional knockout of mitofusin 2 in osteoclasts and submitted the mice to the model of bone loss by ovariectomy, and we observed that conditional knockout osteoclasts mice were protected from trabecular bone loss when compared to control mice. Thus, this work demonstrates that mitofusin 2 stimulates the differentiation of osteoclasts via mitochondrial energy production, and the deletion of mitofusin 2 protects mice from trabecular bone loss. (AU)

• FAPESP's process: 18/17167-9 - Role of mitofusin 2 and mitochondrial dynamics on osteoclasts bone resportion in an Osteoarthritis experimental model
• Grantee: Lucas Gabriel Rodrigues Venturini
• Support Opportunities: Scholarships in Brazil - Doctorate