Role of ER-mitochondria interaction in the mechanism of chemotherapy-induced peripheral neuropathy

Chemotherapy (CT)-induced peripheral neuropathy (CIPN), causing painful paresthesia and numbness, is a common adverse effect of the treatment with different classes of chemotherapeutic agents, known to exert neurotoxic effects over sensory neurons and glial cells. Molecular mechanisms of CIPN remain poorly understood. Noteworthy, mitochondria have been reported as common targets of several CT-based regimens, both in terms of their morphology/motility and of their specific functionality, which is of paramount importance for the maintenance of cellular homeostasis. In the context of mitochondrial function, growing body of evidence highlights the relevance of mitochondria-ER contact sites (MERCS), a highly-organized morpho-functional units involved in response to stress, calcium homeostasis, bioenergetics, autophagy, protein homeostasis and apoptosis. We used cellular models of Schwann cells (MSC80) and sensory neurons (F11) to investigate if mitochondrial dysfunction in CIPN induced by bortezomib (BTZ), a 1 st generation proteasome inhibitor approved as first-line therapy for multiple myeloma, could be linked to alterations of MERC. To assess MERCS alterations, we exploited state-of-the-art split-GFP contact site sensors (SPLICS). Intracellular Ca 2+ handling and mitochondrial membrane potential (ΔΨm) were assessed using both dedicated dyes and genetically-encoded probes. We found that BTZ induced profound changes in mitochondrial network, which was more prominent in MSC80 Schwann cells. Strikingly, BTZ also drastically reduced the amount ER-mitochondria contact sites. In MSC80 Schwann cells, these alterations are accompanied by a strong BTZ-induced depolarization of the mitochondrial membrane. Of note, this depolarization, as well as mitochondrial morphology is partially reverted when the cells co-treated with isoallopregnenolone and allopregnanolone. These compounds belong to the class of neuroactive steroids, that, intriguingly, have already been reported to exert neuroprotective effects over peripheral nerves in different experimental models of peripheral neuropathy, including docetaxel-induced peripheral neuropathy.