Damage to mtDNA in liver injury of patients with extrahepatic cholestasis: the protective effects of mitochondrial transcription factor A.
Oxidative stress and mitochondrial dysfunction are involved in the pathogenesis of chronic liver cholestasis. Mitochondrial DNA (mtDNA) is highly susceptible to oxidative stress and mtDNA damage leads to mitochondrial dysfunction. This study aimed to investigate the mtDNA alterations that occurred during liver injury in patients with extrahepatic cholestasis. Along with an increase in malondialdehyde (MDA) levels and a decrease in ATP levels, extrahepatic cholestatic patients presented a significant increase in mitochondrial 8-hydroxydeoxyguanosine (8-OHdG) levels and decreases in mtDNA copy number, mtDNA transcript levels, and mtDNA nucleoid structure. In L02 cells, glycochenodeoxycholic acid (GCDCA) induced similar damage to the mtDNA and mitochondria. In line with the mtDNA alterations, the mRNA and protein levels of mitochondrial transcription factor A (TFAM) were significantly decreased both in cholestatic patients and in GCDCA-treated L02 cells. Moreover, overexpression of TFAM could efficiently attenuate the mtDNA damage induced by GCDCA in L02 cells. However, without its C-tail, ΔC-TFAM appeared less effective against the hepatotoxicity of GCDCA than the wild-type TFAM. Overall, our study demonstrates that mtDNA damage is involved in liver damage in extrahepatic cholestatic patients. The mtDNA damage is attributable to the loss of TFAM. TFAM has mtDNA-protective effects against the hepatotoxicity of bile acid during cholestasis.
Department of Occupational Health, Third Military Medical University, Chongqing 400038, People's Republic of China.
Shang-Cheng
SC
Xu
Yong-Biao
YB
Chen
Heng
H
Lin
Hui-Feng
HF
Pi
Ni-Xian
NX
Zhang
Chang-Chun
CC
Zhao
Ling
L
Shuai
Min
M
Zhong
Zheng-Ping
ZP
Yu
Zhou
Z
Zhou
Ping
P
Bie
D000255:Adenosine Triphosphate / Q000378:metabolism; D000328:Adult; D001483:Base Sequence; D015153:Blotting, Western; D001651:Cholestasis, Extrahepatic / Q000235:genetics*; D004249:DNA Damage; D017931:DNA Primers; D004272:DNA, Mitochondrial / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000502:physiology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D008099:Liver / Q000293:injuries*; D008297:Male; D008875:Middle Aged; D024101:Mitochondrial Proteins / Q000502:physiology*; D018384:Oxidative Stress; D060888:Real-Time Polymerase Chain Reaction; D014157:Transcription Factors / Q000502:physiology*
D017931:DNA Primers; D004272:DNA, Mitochondrial; D004268:DNA-Binding Proteins; D024101:Mitochondrial Proteins; D014157:Transcription Factors; C422562:mitochondrial transcription factor A; D000255:Adenosine Triphosphate