Effects of a MTND1 mutation on the hepatic metabolism in human induced pluripotent stem cell-derived hepatocytes = MTND1 돌연변이가 유도만능줄기세포 유래 간세포의 대사에 미치는 영향

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Dysfunction of oxidative phosphorylation (OXPHOS) that takes place in mitochondria causes various metabolic disorders in human. However the metabolism of liver in complex I defect was poorly investigated so far. Here I show that hepatic metabolism was changed by energy depletion which causes aggravation of lactic acidosis through AMP-activated protein kinase (AMPK)-dependent pathway in hiPSC-derived hepatocytes from patient having homoplasmic m.3398T>C on mitochondrial-encoded NADH dehydrogenase 1 (MTND1). This in vitro cellular model revealed aberrant mitochondrial characteristics including their morphologies and biogenesis. In addition, glycogen storage level was significantly decreased in patient-derived hepatocytes. Patient iPSC-derived hepatocytes showed decreased Complex I activity, cellular ATP level and NAD+/NADH ratio which mean dysfunction of OXPHOS. Intriguingly, genes related to the conversion of lactate into other metabolite such as glucose and alanine were significantly decreased in patient iPSC-derived hepatocytes. This phenomenon would accelerate lactic acidosis in the patient. Metabolic changes in glycogen storage and lactate turnover were driven by activation of AMPK which is positively regulated by ATP depletion. I rescued phenotypes in glycogen and lactate metabolism by treating an AMPK inhibitor and small interfering RNA (siRNA). These results imply that energy depletion in hepatocytes may result in metabolic shift via AMPK.
Advisors
Han, Yong-Mahnresearcher한용만researcher
Description
한국과학기술원 :생명과학과,
Publisher
한국과학기술원
Issue Date
2016
Identifier
325007
Language
eng
Description

학위논문(박사) - 한국과학기술원 : 생명과학과, 2016.2 ,[viii, 109 p. :]

Keywords

MTND1 defect; induced pluripotent stem cells; hepatocytes; lactic acidosis; AMPK; cellular modeling; MTND1 결손; 유도만능줄기세포; 간세포; 젖산 혈증; 세포 모델링

URI
http://hdl.handle.net/10203/222130
Link
http://library.kaist.ac.kr/search/detail/view.do?bibCtrlNo=648154&flag=dissertation
Appears in Collection
BS-Theses_Ph.D.(박사논문)
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