Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
Theranostics. 2022 Apr 4;12(7):3237-3250. doi: 10.7150/thno.69826. eCollection 2022.
Impaired mitochondrial function contributes to non-alcoholic steatohepatitis (NASH). Acylglycerol kinase (AGK) is a subunit of the translocase of the mitochondrial inner membrane 22 (TIM22) protein import complex. AGK mutation is the leading cause of Sengers syndrome, characterized by congenital cataracts, hypertrophic cardiomyopathy, skeletal myopathy, lactic acidosis, and liver dysfunction. The potential roles and mechanisms of AGK in NASH are not yet elucidated. Hepatic-specific AGK-deficient mice and AGK G126E mutation (AGK kinase activity arrest) mice were on a choline-deficient and high-fat diet (CDAHFD) and a methionine choline-deficient diet (MCD). The mitochondrial function and the molecular mechanisms underlying AGK were investigated in the pathogenesis of NASH. The levels of AGK were significantly downregulated in human NASH liver samples. AGK deficiency led to severe liver damage and lipid accumulation in mice. Aged mice lacking hepatocyte AGK spontaneously developed NASH. AGK G126E mutation did not affect the structure and function of hepatocytes. AGK deficiency, but not AGK G126E mice, aggravated CDAHFD- and MCD-induced NASH symptoms. AGK deficiency-induced liver damage could be attributed to hepatic mitochondrial dysfunction. The mechanism revealed that AGK interacts with mitochondrial respiratory chain complex I subunits, NDUFS2 and NDUFA10, and regulates mitochondrial fatty acid metabolism. Moreover, the AGK DGK domain might directly interact with NDUFS2 and NDUFA10 to maintain the hepatic mitochondrial respiratory chain complex I function. The current study revealed the critical roles of AGK in NASH. AGK interacts with mitochondrial respiratory chain complex I to maintain mitochondrial integrity via the kinase-independent pathway.
线粒体功能障碍导致非酒精性脂肪性肝炎（NASH）。酰基甘油激酶（AGK）是线粒体内膜转位酶 22（TIM22）蛋白导入复合物的一个亚基。AGK 突变是 Sengers 综合征的主要原因，其特征为先天性白内障、肥厚型心肌病、骨骼肌病、乳酸性酸中毒和肝功能障碍。AGK 在 NASH 中的潜在作用和机制尚不清楚。 在胆碱缺乏和高脂肪饮食（CDAHFD）和蛋氨酸胆碱缺乏饮食（MCD）中，肝特异性 AGK 缺陷小鼠和 AGK G126E 突变（AGK 激酶活性停滞）小鼠。研究了 AGK 在 NASH 发病机制中的线粒体功能和分子机制。 在人 NASH 肝组织样本中，AGK 的水平显著下调。AGK 缺乏导致小鼠肝脏严重损伤和脂质积累。缺乏肝细胞 AGK 的老年小鼠自发发展为 NASH。AGK G126E 突变不影响肝细胞的结构和功能。AGK 缺乏而非 AGK G126E 小鼠加剧了 CDAHFD 和 MCD 诱导的 NASH 症状。AGK 缺乏诱导的肝损伤可归因于肝线粒体功能障碍。机制表明，AGK 与线粒体呼吸链复合物 I 亚基 NDUFS2 和 NDUFA10 相互作用，调节线粒体脂肪酸代谢。此外，AGK 的 DGK 结构域可能直接与 NDUFS2 和 NDUFA10 相互作用，以维持肝线粒体呼吸链复合物 I 的功能。 本研究揭示了 AGK 在 NASH 中的关键作用。AGK 通过非激酶依赖性途径与线粒体呼吸链复合物 I 相互作用，维持线粒体完整性。
