College of Life Sciences, TaiKang Center for Life and Medical Sciences, Frontier Science Center for Immunology and Metabolism, Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan University, Wuhan, Hubei, China.
Department of pathology, School of Basic Medicine, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan, Hubei, China.
Nat Commun. 2024 Jan 2;15(1):168. doi: 10.1038/s41467-023-44057-6.
Endoplasmic reticulum (ER)-mitochondria contacts are critical for the regulation of lipid transport, synthesis, and metabolism. However, the molecular mechanism and physiological function of endoplasmic reticulum-mitochondrial contacts remain unclear. Here, we show that Mic19, a key subunit of MICOS (mitochondrial contact site and cristae organizing system) complex, regulates ER-mitochondria contacts by the EMC2-SLC25A46-Mic19 axis. Mic19 liver specific knockout (LKO) leads to the reduction of ER-mitochondrial contacts, mitochondrial lipid metabolism disorder, disorganization of mitochondrial cristae and mitochondrial unfolded protein stress response in mouse hepatocytes, impairing liver mitochondrial fatty acid β-oxidation and lipid metabolism, which may spontaneously trigger nonalcoholic steatohepatitis (NASH) and liver fibrosis in mice. Whereas, the re-expression of Mic19 in Mic19 LKO hepatocytes blocks the development of liver disease in mice. In addition, Mic19 overexpression suppresses MCD-induced fatty liver disease. Thus, our findings uncover the EMC2-SLC25A46-Mic19 axis as a pathway regulating ER-mitochondria contacts, and reveal that impairment of ER-mitochondria contacts may be a mechanism associated with the development of NASH and liver fibrosis.
内质网（ER）-线粒体接触对于脂质运输、合成和代谢的调节至关重要。然而，内质网-线粒体接触的分子机制和生理功能仍不清楚。在这里，我们表明 MICOS（线粒体接触位点和嵴组织系统）复合物的关键亚基 Mic19 通过 EMC2-SLC25A46-Mic19 轴调节 ER-线粒体接触。Mic19 肝特异性敲除（LKO）导致 ER-线粒体接触减少、线粒体脂质代谢紊乱、线粒体嵴解聚和线粒体未折叠蛋白应激反应在小鼠肝细胞中，损害肝线粒体脂肪酸β-氧化和脂质代谢，可能自发引发非酒精性脂肪性肝炎（NASH）和肝纤维化在小鼠中。然而，在 Mic19 LKO 肝细胞中重新表达 Mic19 可阻止小鼠肝病的发展。此外，Mic19 过表达可抑制 MCD 诱导的脂肪肝疾病。因此，我们的发现揭示了 EMC2-SLC25A46-Mic19 轴作为调节 ER-线粒体接触的途径，并表明 ER-线粒体接触的损害可能是与 NASH 和肝纤维化发展相关的机制。
