Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02215, USA.
Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02215, USA.
Cell Metab. 2023 Aug 8;35(8):1356-1372.e5. doi: 10.1016/j.cmet.2023.06.015. Epub 2023 Jul 19.
Liver mitochondria undergo architectural remodeling that maintains energy homeostasis in response to feeding and fasting. However, the specific components and molecular mechanisms driving these changes and their impact on energy metabolism remain unclear. Through comparative mouse proteomics, we found that fasting induces strain-specific mitochondrial cristae formation in the liver by upregulating MIC19, a subunit of the MICOS complex. Enforced MIC19 expression in the liver promotes cristae formation, mitochondrial respiration, and fatty acid oxidation while suppressing gluconeogenesis. Mice overexpressing hepatic MIC19 show resistance to diet-induced obesity and improved glucose homeostasis. Interestingly, MIC19 overexpressing mice exhibit elevated energy expenditure and increased pedestrian locomotion. Metabolite profiling revealed that uracil accumulates in the livers of these mice due to increased uridine phosphorylase UPP2 activity. Furthermore, uracil-supplemented diet increases locomotion in wild-type mice. Thus, MIC19-induced mitochondrial cristae formation in the liver increases uracil as a signal to promote locomotion, with protective effects against diet-induced obesity.
肝脏线粒体经历结构重塑，以维持能量平衡，响应进食和禁食。然而，具体的成分和分子机制驱动这些变化及其对能量代谢的影响仍不清楚。通过比较小鼠蛋白质组学，我们发现禁食通过上调 MICOS 复合物的一个亚基 MIC19 诱导肝脏中特定的线粒体嵴形成。在肝脏中强制表达 MIC19 促进嵴形成、线粒体呼吸和脂肪酸氧化，同时抑制糖异生。过表达肝 MIC19 的小鼠表现出对饮食诱导肥胖的抵抗力和改善的葡萄糖稳态。有趣的是，过表达 MIC19 的小鼠表现出能量消耗增加和步行运动增加。代谢物谱分析显示，由于尿苷磷酸化酶 UPP2 活性增加，这些小鼠的肝脏中尿嘧啶积累。此外，补充尿嘧啶的饮食增加了野生型小鼠的运动。因此，MIC19 诱导的肝脏线粒体嵴形成增加尿嘧啶作为促进运动的信号，对饮食诱导肥胖具有保护作用。
