Chemotherapy-induced peripheral neuropathy (CIPN) is a major cause of dose reduction or discontinuation of an otherwise successful anti-cancer therapy. Patients often experience debilitating chronic pain and numbness due to damage of peripheral nerves. Cellular mechanisms underlying CIPN are not well understood, but disruptions in mitochondrial functions and transport have been posited to contribute to CIPN. However, due to limitations in monitoring mitochondrial transport in vivo, whether disruptions in mitochondrial transport indeed contributes to CIPN remains a major unanswered question. Furthermore, mechanisms for how chemotherapeutics induce mitochondrial transport problems in peripheral neurons are not well understood. This proposal investigates how paclitaxel, a common therapeutic known to cause CIPN, alters mitochondrial transport and contributes to peripheral neuropathy in an intact Drosophila model system. Once established, this approach can be used to screen through other chemotherapeutics on their ability to alter mitochondrial movement and cause CIPN, as well as to identify drugs that could protect against CIPN. Specifically, we will use novel optogenetic tools to address the following questions in vivo. 1) Does paclitaxel alter mitochondrial movement in sensory neurons? 2) Does altered mitochondrial movement contribute to neuropathy? 3) Does paclitaxel elevate mitochondrial ROS and mitochondrial Ca2+ levels to influence mitochondrial movement and cause neuropathy? 4) Does restoring mitochondrial movement prevent neuropathy? Elucidating the link between chemotherapeutics treatment, changes in mitochondrial Ca2+ and ROS contents, and mitochondrial transport and neuropathy will reveal new insights into mechanisms that contribute to CIPN.
This study aims to elucidate the link between altered mitochondrial transport and chemotherapy-induced peripheral neuropathy, as well as to understand mechanisms underlying altered mitochondrial movement. Completion of the proposed study will ultimately lead to therapeutic strategies to alleviate chemotherapy- induced peripheral neuropathy.
