Mitochondria carry out many essential functions in metabolism. A central task is the oxidation of nutrients and the generation of ATP by oxidative phosphorylation. Mitochondrial metabolism needs to be tightly regulated for the cell to respond to changes in ATP demand and nutrient supply. Here, we review how protein lysine acetylation contributes to the regulation of mitochondrial metabolism in insulin target tissues and the insulin-secreting pancreatic β-cell. We summarize recent evidence showing that in pancreatic β-cells, lysine acetylation occurs on a large number of proteins involved in metabolism. Furthermore, we give a brief overview of the molecular mechanism that controls lysine acetylation dynamics. We propose that protein lysine acetylation is an important mechanism for the fine-tuning of mitochondrial activity in β-cells during normal physiology. In contrast, nutrient oversupply, oxidative stress, or inhibition of the mitochondrial deacetylase SIRT3 leads to protein lysine hyperacetylation, which impairs mitochondrial function. By perturbing mitochondrial activity in β-cells and insulin target tissues, protein lysine hyperacetylation may contribute to the development of type 2 diabetes.
