β-Cells Different Vulnerability to the Parkinsonian Neurotoxins Rotenone, 1-Methyl-4-phenylpyridinium (MPP+) and 6-Hydroxydopamine (6-OHDA)

Abstract

Neurotoxins such as rotenone, 1-methyl-4-phenylpyridinium (MPP+) and 6-hydroxydopamine (6-OHDA) are well known for their high toxicity on dopaminergic neurons and are associated with Parkinson’s disease (PD) in murine models and humans. In addition, PD patients often have glucose intolerance and may develop type 2 diabetes (T2D), whereas T2D patients have higher risk of PD compared to general population. Based on these premises, we evaluated the toxicity of these three toxins on pancreatic β-cell lines (INS-1 832/13 and MIN6) and we showed that rotenone is the most potent for reducing β-cells viability and altering mitochondrial structure and bioenergetics in the low nanomolar range, similar to that found in dopaminergic cell lines. MPP+ and 6-OHDA show similar effects but at higher concentration. Importantly, rotenone-induced toxicity was counteracted by α-tocopherol and partially by metformin, which are endowed with strong antioxidative and cytoprotective properties. These data show similarities between dopaminergic neurons and β-cells in terms of vulnerability to toxins and pharmacological agents capable to protect both cell types.

Pancreatic INS-1 β-Cell Response to Thapsigargin and Rotenone: A Comparative Proteomics Analysis Uncovers Key Pathways of β-Cell Dysfunction

“…The IC 50 values of rotenone and thapsigargin were determined as 30 nM and 22 nM, respectively, and were used as final treatment conditions of INS-1 832/13 cells in this study. The IC 50 value of rotenone agreed with previously reported results of the same cell type, 27 while that of thapsigargin was reported as ∼4 μM in the SW-13 and NCI-H295R cell lines. 28 Clearly the IC 50 of thapsigargin is cell line dependent, which reflects each cell line's potential vulnerability to stress.…”

“…The IC 50 value of rotenone agreed with previously reported results of the same cell type, while that of thapsigargin was reported as ∼4 μM in the SW-13 and NCI-H295R cell lines . Clearly the IC 50 of thapsigargin is cell line dependent, which reflects each cell line’s potential vulnerability to stress …”

“…28 Clearly the IC 50 of thapsigargin is cell line dependent, which reflects each cell line's potential vulnerability to stress. 27 Biological Effects of Rotenone and Thapsigargin on INS-1 Cells. Rotenone and thapsigargin cause cell death with distinct classical biological pathways perturbed in their mode of actions.…”

Mitochondrial nanomotion measured by optical microscopy

“…We showed that the addition of 1 μM rotenone to freshly isolated mitochondria led to the complete loss of mitochondrial displacement activity. This loss of activity is most likely due to the toxicity of rotenone as reported in numerous studies (Giordano et al, 2012;Siddiqui et al, 2013;Bavli et al, 2016;Frye et al, 2016;Carli et al, 2021). In addition, our results are in line with a previous study using the AFM-based nanomotion method (Stupar et al, 2017).…”