ROLE OF MITOCHONDRIAL DYNAMICS IN THE DEVELOPMENT OF PACLITAXEL-INDUCED AXONAL DEGENERATION

• Grant number: 23/05626-7
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Effective date (Start): December 01, 2023
• Effective date (End): November 30, 2025
• Field of knowledge: Biological Sciences - Pharmacology
• Principal Investigator: Vanessa Olzon Zambelli
• Grantee: Natália Gabriele Hösch
• Host Institution: Instituto Butantan. Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil

Abstract

Paclitaxel is the standard first-line chemotherapeutic. Although effective in killing cancer cells, it induces peripheral neuropathy in nearly 70% of the patients. The mechanisms involved in paclitaxel-induced axonal degeneration leading to neuropathy are poorly understood. Mitochondria are responsible for maintaining the cellular energy supply and exist as a dynamic and heterogeneous network that undergoes continuous fusion and fission process. GTPases such as Mfn2 and Drp1, which are important for mitochondrial fusion and fission, respectively, regulate mitochondrial plasticity. Considering that neurons have a high metabolic demand and substantial mitochondria density, and that chemotherapy-induced neuropathy often occurs with mitochondrial dysfunction, we hypothesized that an imbalance between Mfn2 and Drp1 levels contributes to the development of axonal degeneration in neuropathic mice. Therefore, in the present study, we will investigate the role of mitochondrial dynamics in the axonal degeneration of mice submitted to paclitaxel-induced neuropathy. The sciatic nerve from wild-type, and conditional knockout mice for Drp1 or Mfn2 in the nociceptors (Drp1flox/Nav1.8Cre, Mfn2flox/Nav1.8Cre) will be used to evaluate the effect of paclitaxel on the: (a) expression of proteins related to the mitochondrial dynamics, by western blot analysis; (b) axonal degeneration, by morphometric analysis and myelin sheath integrity evaluation; (c) expression of proteins related to pro-nociceptive and cell death pathways; (d) production of oxygen reactive species and reactive aldehydes. A better understanding of this process may open perspectives for new approaches to minimize the risks related to chemotherapy-induced axonal degeneration and to better elucidate the mechanisms involved in the mitochondrial homeostasis.