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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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.
Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
Issue Date
2015-12
Language
English
Article Type
Article
Keywords

HEREDITARY OPTIC NEUROPATHY; COMPLEX I DEFICIENCY; HUMAN SOMATIC-CELLS; LACTIC-ACIDOSIS; ELECTRON-TRANSPORT; DIABETES-MELLITUS; HUMAN FIBROBLASTS; SKELETAL-MUSCLE; DEFINED FACTORS; GENE-MUTATIONS

Citation

JOURNAL OF BIOLOGICAL CHEMISTRY, v.290, no.49, pp.29493 - 29505

ISSN
0021-9258
DOI
10.1074/jbc.M115.670364
URI
http://hdl.handle.net/10203/205708
Appears in Collection
BS-Journal Papers(저널논문)
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