Mitochondrial Respiratory Defect Causes Dysfunctional Lactate Turnover via AMP-activated Protein Kinase Activation in Human-induced Pluripotent Stem Cell-derived Hepatocytes.
J Biol Chem
; 290(49): 29493-505, 2015 Dec 04.
Article
in En
| MEDLINE
| ID: mdl-26491018
ABSTRACT
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.3398TâC) 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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Lactic Acid
/
Hepatocytes
/
AMP-Activated Protein Kinases
/
Induced Pluripotent Stem Cells
/
Mitochondria
Type of study:
Etiology_studies
Limits:
Humans
/
Infant
/
Male
Language:
En
Journal:
J Biol Chem
Year:
2015
Document type:
Article