Mitochondrial Respiratory Defect Causes Dysfunctional Lactate Turnover via AMP-activated Protein Kinase Activation in Human-induced Pluripotent Stem Cell-derived Hepatocytes.
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.
From the Department of Biological Sciences, Center for Stem Cell Differentiation, and.
Ilkyun
I
Im
From the Department of Biological Sciences, Center for Stem Cell Differentiation, and.
Mi-Jin
MJ
Jang
From the Department of Biological Sciences.
Seung Ju
SJ
Park
BioMedical Research Center, Korea Advanced Institute of Science and Technology, Daejeon 34141 and.
Sang-Hee
SH
Lee
the Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea.
Jin-Ho
JH
Choi
the Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea.
Han-Wook
HW
Yoo
From the Department of Biological Sciences.
Seyun
S
Kim
From the Department of Biological Sciences, Center for Stem Cell Differentiation, and ymhan@kaist.ac.kr.
Yong-Mahn
YM
Han
D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000140:Acidosis, Lactic / Q000378:metabolism; D002454:Cell Differentiation; D004272:DNA, Mitochondrial / Q000378:metabolism; D004579:Electron Transport; D004789:Enzyme Activation; D005347:Fibroblasts / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology*; D007223:Infant; D019344:Lactic Acid / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008297:Male; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000378:metabolism*; D028361:Mitochondrial Diseases / Q000378:metabolism; D009154:Mutation; D009245:NADH Dehydrogenase / Q000235:genetics; D017354:Point Mutation
D055372:AMP-Activated Protein Kinases; D004272:DNA, Mitochondrial; D006003:Glycogen; D019344:Lactic Acid; D009245:NADH Dehydrogenase; C515075:NADH dehydrogenase subunit 1, human
hepatocyte; induced pluripotent stem cell (iPS cell) (iPSC); lactic acidosis; liver; liver metabolism; mitochondrial disease