GSE136242
Reduced basal insulin secretion from islets isolated from tafazzin deficient mice is associated with reduced mitochondrial function
Tafazzin is a transacylase which causes the content and molecular structure of cardiolipin (CL) to be altered in the inner mitochondrial membrane. The enzymatic machinery responsible for oxidative respiration are localized to the inner mitochondrial membrane and require CL for activity. As a result, tafazzin is critical for maintaining mitochondrial function. In beta-cells, which are the insulin secreting cells in pancreatic islets, mitochondrial function is linked to insulin secretion. We previously established that tafazzin knock-down mice were lean and maintained insulin sensitivity compared to the obese insulin resistant control litter mates. However, it was unknown whether tafazzin deficiency also influenced insulin secretion in the establishment of the lean phenotype. Using X week-old mice, we ascertained that the number of beta-cells was similar between genotypes. Ex vivo insulin secretion under low glucose conditions was reduced (52%) from islets isolated from tafazzin knock-down mice. Consistent with this tafazzin knock-down mice exhibited reduced fasting insulin plasma insulin levels. Measurement of mitochondrial oxygen consumption revealed that basal oxygen consumption was reduced (58%) in islets from tafazzin-deficient animals. The addition of etomoxir, an inhibitor of mitochondrial fatty acid translocation, significantly elevated basal mitochondrial respiration (5-fold) in islets from tafazzin knockdown mice, indicating a significant fatty acid-mediated inhibitory effect. In contrast, etomoxir lacked any measurable effect on control wild-type islets. The altered mitochondrial function identified in taffazin knock-down islets was not associated with reduced CL content or elevated oxyCL species.  Our experiments indicate that tafazzin plays a key role in regulating normal islet beta-cell function. Overall design: RNA-Seq was performed to compare the transcriptome of Tafazzin-knockdown mouse islets to non-transgenic control islets. Islets were isolated from male mice at 3-4 months of age. Approximately 300 Islets were used for each sample that were pooled from 2-3 mice to provide sufficient RNA for analysis.