Effects of Paclitaxel on the Mitochondrial Dynamics of sensorial neurons

• Grant number: 22/02779-4
• Support Opportunities: Scholarships in Brazil - Master
• Start date: January 01, 2023
• End date: February 29, 2024
• Field of knowledge: Biological Sciences - Pharmacology - Biochemical and Molecular Pharmacology
• Principal Investigator: Vanessa Olzon Zambelli
• Grantee: Mariana Caprio Schiess
• Host Institution: Instituto Butantan. Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil

Abstract

Paclitaxel is a chemotherapeutic widely used to treat breast and ovarian cancer. Despite its efficacy against cancer cells, this drug triggers neuropathy in about 70% of the patients. So far, it is known that this drug induces microtubule stabilization and interrupts the axonal transport, leading to ATP impairment and increased oxidative stress. Studies demonstrate a causal correlation between impaired bioenergetic metabolism and the development of neuropathies. However, little is known whether mitochondrial fusion-fission processes are important for bioenergetic metabolism in sensory neurons and, consequently, for the development of pain. Considering that neurons have high metabolic demand and a large number of mitochondria and that chemotherapy-induced neuropathy is often followed by mitochondrial dysfunction, we sought to investigate the role of mitochondrial plasticity (ability to reorganize their morphology and number under stress) in sensory neurons. We hypothesized that the absence of the Mfn2 protein in nociceptors will result in the sustained accumulation of fragmented and dysfunctional mitochondria, contributing to the amplification of neuronal damage resulting from neuropathy. On the other hand, the deletion of Drp1 will result in a protective effect in this model. Thus, the aim of this project is to investigate the role of mitochondrial dynamics on paclitaxel toxicity in sensory cells in culture.