Department of Pharmacology, Tianjin Key Laboratory of Inflammatory Biology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
Department of Pharmacology, Tianjin Key Laboratory of Inflammatory Biology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
Biochem Biophys Res Commun. 2022 Sep 17;621:1-7. doi: 10.1016/j.bbrc.2022.06.092. Epub 2022 Jun 28.
Hepatic gluconeogenesis is crucial for maintaining blood glucose during starvation, and a major contributor for hyperglycemia. Cellular redox state is related to mitochondrial biology and regulates conversion of specific metabolites to glucose. General control of amino acid synthesis 5 (GCN5) like-1 (GCN5L1) is a mitochondria-enriched protein which modulates glucose and amino acid metabolism. Here we show a new regulatory mode of GCN5L1 on gluconeogenesis using lactate and glycerol. We observed GCN5L1 deletion dramatically inhibited glucose production derived from glycerol and lactate, due to increased cytosolic redox state. The underlying mechanism is that GCN5L1 directly binds to the key component of mitochondrial shuttle glycerol phosphate dehydrogenase 2 (GPD2) and modulates its activity. These results have significant implications for understanding the physiological role and regulatory mechanism of mitochondrial shuttle in diabetes development and provide a novel therapeutic potential for diabetes.
肝糖异生对于饥饿时维持血糖水平至关重要，也是导致高血糖的主要原因。细胞氧化还原状态与线粒体生物学有关，并调节特定代谢物向葡萄糖的转化。氨基酸合成 5（GCN5）样蛋白 1（GCN5L1）是一种富含线粒体的蛋白质，可调节葡萄糖和氨基酸代谢。在这里，我们使用乳酸盐和甘油展示了 GCN5L1 对糖异生的新调控模式。我们观察到 GCN5L1 缺失显著抑制了甘油和乳酸盐衍生的葡萄糖生成，这是由于细胞浆氧化还原状态增加所致。其潜在机制是 GCN5L1 直接与线粒体穿梭甘油磷酸脱氢酶 2（GPD2）的关键组成部分结合并调节其活性。这些结果对于理解线粒体穿梭在糖尿病发展中的生理作用和调控机制具有重要意义，并为糖尿病的治疗提供了新的潜在靶点。
