| Summary: | Abstract Lack of efficient insulin secretion from the pancreas can lead to impaired glucose tolerance (IGT), prediabetes, and diabetes. We have previously identified two IGT-associated single nucleotide polymorphisms (SNPs) rs62212118 and rs13052524 located at two overlapping genes: MRPS6 and SLC5A3. In this study, we show that MRPS6 but not SLC5A3 regulates glucose-stimulated insulin secretion (GSIS) in primary human β-cell and a mouse pancreatic insulinoma β-cell line. Data mining and biochemical studies reveal that MRPS6 is positively regulated by the mitochondrial unfolded protein response (UPRmt), but feedback inhibits UPRmt. Disruption of such feedback by MRPS6 knockdown causes UPRmt hyperactivation in high glucose conditions, hence elevated ROS levels, increased apoptosis, and impaired GSIS. Conversely, MRPS6 overexpression reduces UPRmt, mitigates high glucose-induced ROS levels and apoptosis, and enhances GSIS in an ATF5-dependent manner. Consistently, UPRmt up-regulation or down-regulation by modulating ATF5 expression is sufficient to decrease or increase GSIS. The negative role of UPRmt in GSIS is further supported by analysis of public transcriptomic data from murine islets. In all, our studies identify MRPS6 and UPRmt as novel modulators of GSIS and apoptosis in β-cells, contributing to our understanding of the molecular and cellular mechanisms of IGT, prediabetes, and diabetes.
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