PMID- 26491018
OWN - NLM
STAT- MEDLINE
DCOM- 20160419
LR  - 20220317
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 290
IP  - 49
DP  - 2015 Dec 4
TI  - Mitochondrial Respiratory Defect Causes Dysfunctional Lactate Turnover via 
      AMP-activated Protein Kinase Activation in Human-induced Pluripotent Stem 
      Cell-derived Hepatocytes.
PG  - 29493-505
LID - 10.1074/jbc.M115.670364 [doi]
AB  - 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.
CI  - (c) 2015 by The American Society for Biochemistry and Molecular Biology, Inc.
FAU - Im, Ilkyun
AU  - Im I
AD  - From the Department of Biological Sciences, Center for Stem Cell Differentiation, 
      and.
FAU - Jang, Mi-Jin
AU  - Jang MJ
AD  - From the Department of Biological Sciences, Center for Stem Cell Differentiation, 
      and.
FAU - Park, Seung Ju
AU  - Park SJ
AD  - From the Department of Biological Sciences.
FAU - Lee, Sang-Hee
AU  - Lee SH
AD  - BioMedical Research Center, Korea Advanced Institute of Science and Technology, 
      Daejeon 34141 and.
FAU - Choi, Jin-Ho
AU  - Choi JH
AD  - the Department of Pediatrics, Asan Medical Center Children's Hospital, University 
      of Ulsan College of Medicine, Seoul 05505, Republic of Korea.
FAU - Yoo, Han-Wook
AU  - Yoo HW
AD  - the Department of Pediatrics, Asan Medical Center Children's Hospital, University 
      of Ulsan College of Medicine, Seoul 05505, Republic of Korea.
FAU - Kim, Seyun
AU  - Kim S
AD  - From the Department of Biological Sciences.
FAU - Han, Yong-Mahn
AU  - Han YM
AD  - From the Department of Biological Sciences, Center for Stem Cell Differentiation, 
      and ymhan@kaist.ac.kr.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20151021
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (DNA, Mitochondrial)
RN  - 33X04XA5AT (Lactic Acid)
RN  - 9005-79-2 (Glycogen)
RN  - EC 1.6.99.3 (NADH Dehydrogenase)
RN  - EC 2.7.11.31 (AMP-Activated Protein Kinases)
RN  - EC 7.1.1.2 (MT-ND1 protein, human)
SB  - IM
MH  - AMP-Activated Protein Kinases/*metabolism
MH  - Acidosis, Lactic/metabolism
MH  - Cell Differentiation
MH  - DNA, Mitochondrial/metabolism
MH  - Electron Transport
MH  - Enzyme Activation
MH  - Fibroblasts/metabolism
MH  - Glycogen/metabolism
MH  - Hepatocytes/cytology/*metabolism
MH  - Humans
MH  - Induced Pluripotent Stem Cells/*cytology
MH  - Infant
MH  - Lactic Acid/*metabolism
MH  - Liver/metabolism
MH  - Male
MH  - Microscopy, Electron, Transmission
MH  - Mitochondria/*metabolism
MH  - Mitochondrial Diseases/metabolism
MH  - Mutation
MH  - NADH Dehydrogenase/genetics
MH  - Point Mutation
PMC - PMC4705950
OTO - NOTNLM
OT  - hepatocyte
OT  - induced pluripotent stem cell (iPS cell) (iPSC)
OT  - lactic acidosis
OT  - liver
OT  - liver metabolism
OT  - mitochondrial disease
EDAT- 2015/10/23 06:00
MHDA- 2016/04/20 06:00
PMCR- 2016/12/04
CRDT- 2015/10/23 06:00
PHST- 2015/06/04 00:00 [received]
PHST- 2015/10/23 06:00 [entrez]
PHST- 2015/10/23 06:00 [pubmed]
PHST- 2016/04/20 06:00 [medline]
PHST- 2016/12/04 00:00 [pmc-release]
AID - S0021-9258(20)39562-4 [pii]
AID - M115.670364 [pii]
AID - 10.1074/jbc.M115.670364 [doi]
PST - ppublish
SO  - J Biol Chem. 2015 Dec 4;290(49):29493-505. doi: 10.1074/jbc.M115.670364. Epub 
      2015 Oct 21.