Chemotherapy-induced peripheral neuropathy: a focus on ER-mitochondrial interactions

Chemotherapy (CT)-induced peripheral neuropathy (CIPN) is a common adverse effect of the treatment with different classes of chemotherapeutic agents and it manifests as a set of sensory-related symptoms. It is estimated that around 60-70% of patients undergoing CT experience these symptoms, that might be so disabling to force them to CT dose reduction or treatment withdrawal. At the cellular level, CT is well known to exert neurotoxic effects over sensory neurons and peripheral glial cells, but the precise molecular mechanisms by which it induces damage to these cells are poorly understood. Noteworthy, mitochondria have been reported as targets of several chemo-based regimens, both in terms of their morphology/motility and of their specific functionality, essential for the maintenance of cellular homeostasis. In the context of mitochondria, growing body of evidence highlights the relevance of ER- mitochondria interaction, which takes place at the level of complex morpho-functional units known as mitochondria-ER contact sites (MERCS). Therefore, a promising strategy to unveil CIPN molecular mechanisms could be represented by a focused analysis of the possible effects of antineoplastic drugs at the level of MERCS in both sensory neurons and glial cells. To achieve this goal, we are investigating MERCS structure and functionality upon treatment with different classes of chemotherapeutic agents, firstly in F11 and Msc80 cell lines (chosen as models for sensory neurons and peripheral glial cells, respectively) and next in primary cells. Here we provide preliminary insights of dramatic alterations observed in mitochondria and MERCS distribution in Msc80 after treatment with bortezomib (BTZ), despite the mechanism by which the drug exerts these effects still needs to be fully elucidated. Then, once identified possible mechanisms altered by CT, we will try to correct them by employing neuroactive steroids, that have been reported to have beneficial effects over neurons in different subtypes of peripheral neuropathies.