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2014 ; 289
(49
): 34074-88
Nephropedia Template TP
Yu T
; Wang L
; Lee H
; O'Brien DK
; Bronk SF
; Gores GJ
; Yoon Y
J Biol Chem
2014[Dec]; 289
(49
): 34074-88
PMID25342755
show ga
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.
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