Abstract
An imbalance in mitochondrial dynamics induced by oxidative stress may lead to hepatocyte epithelial mesenchymal transition (EMT) and liver fibrosis. However, the underlying molecular mechanisms have not been fully elucidated. This study investigated the role of mitochondrial dynamics in hepatocyte EMT and liver fibrosis using an in vitro human (L-02 cells, hepatic cell line) and an in vivo mouse model of liver fibrosis. Findings showed that oxidative stress-induced mitochondrial DNA damage was associated with abnormal mitochondrial fission and hepatocyte EMT. The reactive oxygen species (ROS) scavengers apocynin and mito-tempo effectively attenuated carbon tetrachloride (CCl4)-induced abnormal mitochondrial fission and liver fibrosis. Restoring mitochondrial biogenesis attenuated hepatocyte EMT. Oxidative stress-induced abnormal hepatocyte mitochondrial fission events by a mechanism that involved the down regulation of PGC-1α. PGC-1α knockout mice challenged with CCl4 had increased abnormal mitochondrial fission and more severe liver fibrosis than wild type mice. These results indicate that PGC-1α has a protective role in oxidative stress-induced-hepatocyte EMT and liver fibrosis.
Highlights
Liver fibrosis occurs in many forms of liver disease, including hepatitis and chronic alcoholism, and results in scarring and damage to the liver[1,2,3]
Cells were harvested for analysis of PGC-1α, Drp[1], Fig. 1 reactive oxygen species (ROS) scavengers attenuate the progression of liver fibrosis. a Apocynin and mito-tempo treatment protocol. b Immunohistochemistry showing 3-nitrotyrosine, α-SMA and collagen I expression were increased in liver tissue derived from mice challenged with CCl4 for 8 weeks
Liver fibrosis was effectively reversed by ROS scavengers A mouse model of liver fibrosis was established after
Summary
Liver fibrosis occurs in many forms of liver disease, including hepatitis and chronic alcoholism, and results in scarring and damage to the liver[1,2,3]. Liver fibrosis is a wound-healing response that is characterized by excessive deposition of extracellular matrix (ECM) proteins, hepatocyte damage, distortion of the hepatic lobules, and changes in the vascular architecture[4]. Overproduction of reactive oxygen species (ROS) results in oxidative stress, which is involved in the pathophysiology of cardiovascular disease, cancer, and Tightly regulated cycles of fusion and fission adapt mitochondrial morphology to the metabolic needs of a cell, such that mitochondrial fusion increases metabolic efficiency, while mitochondrial fission favors uncoupled respiration[11]. Mitochondrial fusion is stimulated by energy demand and stress. Stress-induced fusion allows mitochondria to share components and compensate for defect protein complexes or DNA sequences that are essential for ATP production.
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