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Association between mitochondrial and nuclear DNA damages and cellular senescence in the patients with biliary atresia undergoing Kasai portoenterostomy and liver transplantation

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Abstract

Biliary atresia (BA) is a cholestatic disease with extrahepatic bile duct obstruction that requires early surgical intervention and occasionally liver transplantation (LT). Accumulation of toxic bile acids induces oxidative stress that results in cell damage, such as cell senescence, mitochondrial dysfunction and others. However, details of their reciprocal association and clinical significance are unexplored. Therefore, we used immuno-localization of markers for cell senescence (p16 and p21), nuclear double-strand DNA damage (γH2AX), autophagy (p62), and mtDNA damage (mtDNA copy number) in patients with BA who underwent Kasai portoenterostomy (KP) and LT. We studied liver biopsy specimens from 54 patients with BA, 14 who underwent LT and 11 from the livers of neonates and infants obtained at autopsy. In hepatocytes, p21 expression was significantly increased in KP. In cholangiocytes, p16 expression was significantly increased in LT, and p21 expression was significantly increased in KP. p62 expression was significantly increased in the KP hepatocytes and LT cholangiocytes. Furthermore, mtDNA copy number significantly decreased in KP and LT compared with the control. Cell senescence and mitochondrial DNA damage progression were dependent on the BA clinical stages and could possibly serve as the markers of indication of LT.

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Abbreviations

ALT:

Alanine transaminase

BA:

Biliary atresia

ChE:

Cholinesterase

D.Bil:

Direct bilirubin

DR:

Ductular reaction

FFPE:

Formalin-fixed paraffin-embedded

H&E:

Hematoxylin–eosin

IHC:

Immunohistochemistry

KP:

Kasai portoenterostomy

LT:

Liver transplantation

mtDNA:

Mitochondrial DNA

mtDNAcn:

Mitochondrial DNA copy number

NL:

Non-pathological liver

Plt:

Platelet

ROS:

Reactive oxygen species

T.Bil:

Total bilirubin

8-OHdG:

8-Hydroxydeoxyguanosine

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Acknowledgements

We appreciate the skillful technical assistance of Mr. Katsuhiko Ono, Mr. Yoshiaki Onodera (Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan) and Ms. Yayoi Aoyama (Department of Pathology, Tohoku University Hospital, Sendai, Japan). We would like to thank Editage (www.editage.com) for English language editing. Supported by Health and Labor Sciences Research Grants (19FC1008).

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Authors and Affiliations

  1. Department of Pathology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, 980-8575, Japan

    Yudai Nakajima, Yuto Yamazaki, **n Gao, Masatoshi Hashimoto & Hironobu Sasano

  2. Department of Pediatric Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan

    Yudai Nakajima, Masatoshi Hashimoto, Masaki Nio & Motoshi Wada

  3. Tohoku Kousai Hospital, Sendai, Japan

    Masaki Nio

  4. Department of Pathology, Tohoku University Hospital, Sendai, Japan

    Fumiyoshi Fujishima & Hironobu Sasano

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Nakajima, Y., Yamazaki, Y., Gao, X. et al. Association between mitochondrial and nuclear DNA damages and cellular senescence in the patients with biliary atresia undergoing Kasai portoenterostomy and liver transplantation. Med Mol Morphol 55, 131–145 (2022). https://doi.org/10.1007/s00795-022-00314-z

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