Decreasing mitochondrial fission alleviates hepatic steatosis in a murine model of nonalcoholic fatty liver disease

Chad A. Galloway, Hakjoo Lee, Paul S. Brookes, Yisang Yoon

Research output: Contribution to journalArticle

37 Scopus citations

Abstract

Mitochondria produce the majority of cellular ATP through oxidative phosphorylation, and their capacity to do so is influenced by many factors. Mitochondrial morphology is recently suggested as an important contributor in controlling mito-chondrial bioenergetics. Mitochondria divide and fuse continuously, which is affected by environmental factors, including metabolic alterations. Underscoring its bioenergetic influence, altered mitochon-drial morphology is reported in tissues of patients and in animal models of metabolic dysfunction. In this study, we found that mito-chondrial fission plays a vital role in the progression of nonalcoholic fatty liver disease (NAFLD). The development of hepatic steatosis, oxidative/nitrative stress, and hepatic tissue damage, induced by a high-fat diet, were alleviated in genetically manipulated mice suppressing mitochondrial fission. The alleviation of steatosis was recapitulated in primary hepatocytes with the inhibition of mitochondrial fission. Mechanistically, our study indicates that fission inhibition enhances proton leak under conditions of free fatty acid incubation, implicating bioenergetic change through manipulating mitochondrial fission. Taken together, our results suggest a mechanistic role for mitochondrial fission in the etiology of NAFLD. The efficacy of decreasing mitochondrial fission in the suppression of NAFLD suggests that mitochondrial fission represents a novel target for therapeutic treatment of NAFLD.

Original languageEnglish (US)
Pages (from-to)G632-G641
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume307
Issue number6
DOIs
StatePublished - Sep 15 2014

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Keywords

  • Bioenergetics
  • Dynamin-related protein 1
  • Mitochondrial morphology
  • Oxidative stress
  • Proton leak

ASJC Scopus subject areas

  • Physiology
  • Hepatology
  • Gastroenterology
  • Physiology (medical)

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