Mitochondrial Respiratory Defect Causes Dysfunctional Lactate Turnover via AMP-activated Protein Kinase Activation in Human-induced Pluripotent Stem Cell-derived Hepatocytes
Mitochondrial Respiratory Defect Causes Dysfunctional Lactate Turnover via AMP-activated Protein Kinase Activation in Human-induced Pluripotent Stem Cell-derived Hepatocytes
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DOI：
10.1074/jbc.m115.670364
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发表时间：
2015-12-04
影响因子：
4.8
通讯作者：
Han, Yong-Mahn
中科院分区：
文献类型：
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作者：
Im, Ilkyun;Jang, Mi-jin;Han, Yong-Mahn
有缺陷的线粒体呼吸链复合体（DMRC）导致人类的各种代谢紊乱。然而，DMRC在肝脏中的病理生理学仍不清楚。为了理解体外DMRC病理生理学，从DMRC患者的真皮成纤维细胞产生DMRC诱导的多能干细胞，所述DMRC患者在核糖核酸编码的NADH脱氢酶1（MTND 1）基因中具有同质突变（m.3398T -> C）并且在体外分化成肝细胞（DMRC肝细胞）。DMRC肝细胞的线粒体特征、NAD（+）/NADH比值、糖原储备水平、乳酸周转率和AMPK活性均出现异常。有趣的是，DMRC肝细胞中的低糖原储存和乳酸周转相关基因的转录通过抑制AMPK活性而恢复。因此，AMPK激活导致DMRC肝细胞中糖原储存和乳酸周转方面的代谢变化。这些数据首次表明，能量消耗可能导致DMRC患者通过肝脏中AMPK的乳酸摄取减少而导致乳酸酸中毒。
A defective mitochondrial respiratory chain complex (DMRC) causes various metabolic disorders in humans. However, the pathophysiology of DMRC in the liver remains unclear. To understand DMRC pathophysiology in vitro, DMRC-induced pluripotent stem cells were generated from dermal fibroblasts of a DMRC patient who had a homoplasmic mutation (m.3398T -> C) in the mitochondrion-encoded NADH dehydrogenase 1 (MTND1) gene and that differentiated into hepatocytes (DMRC hepatocytes) in vitro. DMRC hepatocytes showed abnormalities in mitochondrial characteristics, the NAD(+)/NADH ratio, the glycogen storage level, the lactate turnover rate, and AMPK activity. Intriguingly, low glycogen storage and transcription of lactate turnover-related genes in DMRC hepatocytes were recovered by inhibition of AMPK activity. Thus, AMPK activation led to metabolic changes in terms of glycogen storage and lactate turnover in DMRC hepatocytes. These data demonstrate for the first time that energy depletion may lead to lactic acidosis in the DMRC patient by reduction of lactate uptake via AMPK in liver.