Abstract
Mitochondria frequently change their shape through fission and fusion in response to physiological stimuli as well as pathological insults. Disrupted mitochondrial morphology has been observed in cholestatic liver disease. However, the role of mitochondrial shape change in cholestasis is not defined. In this study, using in vitro and in vivo models of bile acid-induced liver injury, we investigated the contribution of mitochondrial morphology to the pathogenesis of cholestatic liver disease. We found that the toxic bile salt glycochenodeoxycholate (GCDC) rapidly fragmented mitochondria, both in primary mouse hepatocytes and in the bile transporter-expressing hepatic cell line McNtcp.24, leading to a significant increase in cell death. GCDC-induced mitochondrial fragmentation was associated with an increase in reactive oxygen species (ROS) levels. We found that preventing mitochondrial fragmentation in GCDC by inhibiting mitochondrial fission significantly decreased not only ROS levels but also cell death. We also induced cholestasis in mouse livers via common bile duct ligation. Using a transgenic mouse model inducibly expressing a dominant-negative fission mutant specifically in the liver, we demonstrated that decreasing mitochondrial fission substantially diminished ROS levels, liver injury, and fibrosis under cholestatic conditions. Taken together, our results provide new evidence that controlling mitochondrial fission is an effective strategy for ameliorating cholestatic liver injury.
Highlights
Bile acid-induced hepatocyte injury causes cholestatic liver disease
Using transgenic mice expressing a dominant-negative form of DLP1 in the liver, we showed that decreasing mitochondrial fission significantly diminished the liver injury and fibrosis after bile duct ligation
Toxic Bile Salt GCDC Causes Cell Death and Induces Mitochondrial Fragmentation in Primary Hepatocytes—Impaired bile flow during cholestasis causes the accumulation of bile acids in hepatocytes and leads to cell death [1]
Summary
Bile acid-induced hepatocyte injury causes cholestatic liver disease. Results: Inhibiting mitochondrial fission prevents bile acid-induced hepatocyte death, and liver-specific decrease of mitochondrial fission in vivo limits bile duct ligation-induced liver injury and fibrosis. It is likely that both apoptotic and necrotic cell death are present in chronic cholestatic diseases, depending on the length, cause, and complications of the disease [1, 5] Both necrosis and apoptosis involve mitochondria; mitochondrial dysfunction and overproduction of reactive oxygen species (ROS) play a key role in the progression of chronic liver diseases. We found that a toxic bile salt induces mitochondrial fragmentation through the function of DLP1, which is accompanied by ROS increase and cell death. Using transgenic mice expressing a dominant-negative form of DLP1 in the liver, we showed that decreasing mitochondrial fission significantly diminished the liver injury and fibrosis after bile duct ligation. Our data provide new in vivo evidence that limiting mitochondrial fission is an effective strategy for ameliorating cholestatic liver injury
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