The mitochondria-targeted antioxidant MitoQ attenuates liver fibrosis in mice

Hasibur Rehman, Qinlong Liu, Yasodha Krishnasamy, Zengdun Shi, Venkat K. Ramshesh, Khujista Haque, Rick G. Schnellmann, Michael P. Murphy, John J. Lemasters, Don C. Rockey, Zhi Zhong

Research output: Contribution to journalArticlepeer-review

53 Scopus citations

Abstract

Oxidative stress plays an essential role in liver fibrosis. This study investigated whether MitoQ, an orally active mitochondrial antioxidant, decreases liver fibrosis. Mice were injected with corn oil or carbon tetrachloride (CCl4, 1:3 dilution in corn oil; 1 μl/g, ip) once every 3 days for up to 6 weeks. 4-Hydroxynonenal adducts increased markedly after CCl4 treatment, indicating oxidative stress. MitoQ attenuated oxidative stress after CCl4. Collagen 1α1 mRNA and hydroxyproline increased markedly after CCl4 treatment, indicating increased collagen formation and deposition. CCl4 caused overt pericentral fibrosis as revealed by both the sirius red staining and second harmonic generation microscopy. MitoQ blunted fibrosis after CCl4. Profibrotic transforming growth factor-β1 (TGF-β1) mRNA and expression of smooth muscle α-actin, an indicator of hepatic stellate cell (HSC) activation, increased markedly after CCl4 treatment. Smad 2/3, the major mediator of TGF-β fibrogenic effects, was also activated after CCl4 treatment. MitoQ blunted HSC activation, TGF-β expression, and Smad2/3 activation after CCl4 treatment. MitoQ also decreased necrosis, apoptosis and inflammation after CCl4 treatment. In cultured HSCs, MitoQ decreased oxidative stress, inhibited HSC activation, TGF-β1 expression, Smad2/3 activation, and extracellular signal-regulated protein kinase activation. Taken together, these data indicate that mitochondrial reactive oxygen species play an important role in liver fibrosis and that mitochondria-targeted antioxidants are promising potential therapies for prevention and treatment of liver fibrosis.

Original languageEnglish (US)
Pages (from-to)14-27
Number of pages14
JournalInternational Journal of Physiology, Pathophysiology and Pharmacology
Volume8
Issue number1
StatePublished - 2016
Externally publishedYes

Keywords

  • Antioxidant
  • Hepatic stellate cell
  • Liver fibrosis
  • Mitochondria
  • MitoQ
  • Oxidative stress

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Physiology
  • Physiology (medical)

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