A NEET Way to Impair Mitochondrial Function in α- and β-Cells.

Abstract

Glucose homeostasis requires a carefully orchestrated balance between the release of insulin and glucagon by β- and α-cells, respectively, in pancreatic islets. During fasting, the rate of insulin secretion falls to slow glucose utilization, whereas that of glucagon secretion rises to promote gluconeogenesis, thereby preventing hypoglycemia. After a mixed meal, glucose stimulates insulin secretion while inhibiting glucagon secretion. This “yin and yang” pattern of β- and α-cell activation and inhibition is very important for the regulation of glucose homeostasis, and dysregulation of pancreatic hormones is a prominent feature of diabetes. It has been appreciated for some time that mitochondrial dysfunction is observed in the β-cells of patients with diabetes (1,2) and that mitochondrial DNA mutations in humans or targeted disruption of mitochondrial genome maintenance in mice are sufficient to drive β-cell dysfunction (3,4). However, the primary mitochondrial defects studied in β-cells to date have generally been severe, and neither the cause nor the consequences of the milder mitochondrial dysfunction observed in the majority of patients with diabetes have been firmly established. Moreover, the consequences of mitochondrial dysfunction in α-cells are relatively unexplored. In this issue of Diabetes , Kusminski et al. (5) introduce tetracycline-inducible expression mitochondrial protein mitoNEET in α- or β-cells as a model of graded mitochondrial dysfunction. MitoNEET (named for its COOH-terminal Asn-Glu-Glu-Thr amino acid sequence) is a mitochondrial outer membrane protein that is oriented toward the cytoplasm and binds iron–sulfur clusters (6,7). Its …