Journal
APOPTOSIS
Volume 24, Issue 11-12, Pages 879-891Publisher
SPRINGER
DOI: 10.1007/s10495-019-01566-4
Keywords
beta-Cells; Mitochondrial complex I; Rotenone; Apoptosis; Type 1 diabetes mellitus
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Type 1 diabetes mellitus (T1DM) is caused by pancreatic beta-cell dysfunction and apoptosis, with consequent severe insulin deficiency. Thus, beta-cell protection may be a primary target in the treatment of T1DM. Evidence has demonstrated that defective mitochondrial function plays an important role in pancreatic beta-cell dysfunction and apoptosis; however, the fundamental effect of mitochondrial complex I action on beta-cells and T1DM remains unclear. In the current study, the pancreas protective effect of complex I inhibitor rotenone (ROT) and its potential mechanism were assessed in a streptozotocin (STZ)-induced mouse model of T1DM and in cultured mouse pancreatic beta-cell line, Min6. ROT treatment exerted a hypoglycemic effect, restored the insulin level, and decreased inflammation and cell apoptosis in the pancreas. In vitro experiments also showed that ROT decreased STZ- and inflammatory cytokines-induced beta-cell apoptosis. These protective effects were accompanied by attenuation of reactive oxygen species, increased mitochondrial membrane potential, and upregulation of transcriptional coactivator PPAR alpha coactivator 1 alpha (PGC-1 alpha)-controlled mitochondrial biogenesis. These findings suggest that mitochondrial complex I inhibition may represent a promising strategy for beta-cell protection in T1DM.
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