Mitochondrial Respiratory Defect Causes Dysfunctional Lactate Turnover via AMP-activated Protein Kinase Activation in Human-induced Pluripotent Stem Cell-derived Hepatocytes

• Published in: The Journal of biological chemistry 2015-12, Vol.290 (49), p.29493-29505
• Main Authors: Im, Ilkyun, Jang, Mi-jin, Park, Seung Ju, Lee, Sang-Hee, Choi, Jin-Ho, Yoo, Han-Wook, Kim, Seyun, Han, Yong-Mahn
• Format: Article
• Language: English
• Subjects: Acidosis, Lactic - metabolism; AMP-Activated Protein Kinases - metabolism; Cell Biology; Cell Differentiation; DNA, Mitochondrial - metabolism; Electron Transport; Enzyme Activation; Fibroblasts - metabolism; Glycogen - metabolism; hepatocyte; Hepatocytes - cytology; Hepatocytes - metabolism; Humans; induced pluripotent stem cell (iPS cell) (iPSC); Induced Pluripotent Stem Cells - cytology; Infant; Lactic Acid - metabolism; lactic acidosis; liver; Liver - metabolism; Male; Microscopy, Electron, Transmission; Mitochondria - metabolism; mitochondrial disease; Mitochondrial Diseases - metabolism; Mutation; NADH Dehydrogenase - genetics; Point Mutation
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M115.670364

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. Background: Metabolic influences of defective mitochondrial respiration in hepatocytes remain elusive. Results: Mutation of mitochondrion-encoded NADH dehydrogenase 1 enhanced the activity of AMP-activated protein kinase (AMPK) and decreased lactate turnover in differentiated hepatocytes. Conclusion: Dysfunctional mitochondria in the hepatocytes may be responsible for lactic acidosis. Significance: This study provides new insight on the role of AMPK in lactic acidosis caused by mitochondrial dysfunction.