CHEMOTHERAPY-INDUCED ER-MITOCHONDRIAL ALTERATIONS IN SCHWANN CELLS: A POSSIBLE THREAT FOR LIPID HOMEOSTASIS IN THE PERIPHERAL NERVOUS SYSTEM?

Anticancer treatment with the proteasome inhibitor bortezomib (BTZ) frequently leads to painful peripheral neuropathies, whose pathogenesis is reportedly linked to mitochondrial dysfunction. Mitochondrial homeostasis is highly dependent on the interactions that these organelles establish with the endoplasmic reticulum (ER) at mitochondria-ER contact sites (MERCS), central hubs for the coordination of pivotal physiological processes. Among these, one of the most relevant is interorganellar lipid transfer, crucial for the regulation of intracellular lipid homeostasis.
Here, we propose MERCS as key targets of BTZ-induced toxicity, particularly in Schwann cells, primary drivers of lipid metabolism in the peripheral nervous system (PNS).
Accordingly, we tested the MERCS-related effects of BTZ on the immortalized Schwann cell line MSC80, employing different imaging approaches (confocal, transmission electron microscopy, holotomography), lipidomic analysis and western blotting. In parallel, we investigated the beneficial effects of the neuroactive steroid allopregnanolone (ALLO) against BTZ-induced toxicity, with a specific focus on MERCS.
We found that BTZ induces a drastic reduction in the number of MERCS and an overall increase in ER-mitochondrial distance, accompanied by a significant alteration of the mitochondrial network and distribution. In line with these observations, we demonstrated that BTZ alters the lipidomic profile of MSC80, impairing organelle-specific lipid handling and leading to aberrant neutral lipid accumulation and storage into lipid droplets. Intriguingly, the abovementioned parameters were significantly prevented with ALLO co-treatment.
This study provides evidence that BTZ impairs MERCS ultrastructure and functionality in Schwann cells, specifically by affecting their ability to maintain a proper intracellular lipid homeostasis in the PNS.