The ubiquitin proteasomal system and autophagic pathway are two main protein degradation systems in eukaryotic cells. Inhibition of the proteasomal system with proteasome inhibitors for cancer treatment can cause neurotoxic side effects. In this study, we investigated neurotoxic side effects of bortezomib (BTZ) and carfilzomib (CFZ) in a human neuronal cell model. Inhibition of proteasome with BTZ upregulated autophagy receptor protein p62 level. BTZ caused reduced mitochondrial mass per cell in a greater extent than CFZ. BTZ caused more clustering of mitochondria than CFZ. In conclusion, mitochondrial toxicity and autophagic upregulation with BTZ may be the reason for more severe neurotoxic profile than CFZ.