Role of Mitochondrial Dynamics on the Effect of Paclitaxel on Mouse Sensory Neurons

• Grant number: 23/13449-8
• Support Opportunities: Scholarships in Brazil - Master
• Start date: February 01, 2024
• End date: November 30, 2025
• Field of knowledge: Biological Sciences - Pharmacology - Biochemical and Molecular Pharmacology
• Principal Investigator: Vanessa Olzon Zambelli
• Grantee: Vitória Carvalho Troitiño
• Host Institution: Instituto Butantan. Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil

Abstract

Paclitaxel is a chemotherapy drug widely used to eliminate breast and ovarian cancer. Despite being effective against cancer cells, this chemotherapy induces neuropathy in about 70% of the patients. It is well known that this drug induces microtubules stabilization, interrupting axonal transport, which reduces the supply of ATP and promotes oxidative stress. Mitochondria are critical organelles to supply the cellular energy demand and continuously undergo fusion and fission processes. These opposing processes work together to maintain the shape, size and number of mitochondria. GTPases such as mitofusin 2 and dynamin-related protein (Mfn2, important in mitochondrial fusion and Drp1, important in mitochondrial fission) are important for the regulation of mitochondrial plasticity. Studies demonstrate a causal correlation between impaired bioenergetic metabolism and the development of neuropathies. Considering that neurons have a high metabolic demand and a large amount of mitochondria, and that chemotherapy-induced neuropathy is often accompanied by mitochondrial dysfunction, our hypothesis is 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. On the other hand, the Drp1 deletion will result in a protective effect in this model. Thus, the aim of this project is to investigate the role of neuronal mitochondrial dynamics on paclitaxel-induced neurotoxicity. Therefore, the experiments will be conducted in primary culture of the root ganglion dorsal (DRG) of wildtype mice and mice with nociceptor-specific deletion of DRP1 or MFN2 (Drp1flox/Nav1.8Cre, Mfn2flox/Nav1.8 Cre), treated with different concentrations of paclitaxel. The specific aims are to evaluate: (a) the role of mitochondrial fusion and fission on the organization of the cytoskeleton, by confocal microscopy; (b) the mitochondrial morphology, fragmentation profile and oxidative stress, by electron microscopy, mitotracker and mitosox. A better understanding of this process may contribute to the development and use of new strategies to minimize the risks caused by chemotherapy-induced peripheral neuropathy and elucidate the mechanisms involved in mitochondrial homeostasis.