Abstract
Retention of bile acids within the liver is a primary factor in the pathogenesis of cholestatic liver disorders, which are more common in human infants. The objective of this study was to evaluate developmental changes in mitochondrial factors involved in bile acid-induced hepatocyte injury. Hepatic mitochondria from adult rats (aged 9 wk) underwent a mitochondrial permeability transition (MPT) and release of cytochrome c upon exposure to glycochenodeoxycholic acid. In contrast, mitochondria from young rats (age 6–36 d) were resistant to MPT induction and cytochrome c release. Neither mitochondrial levels of MPT-associated proteins (voltage-dependent anion channel, cyclophilin D, or adenine nucleotide translocase), Bcl-2 family proteins, nor antioxidant enzymes explained this resistance. Mitochondria from young rats contained 2- to 3-fold higher α-tocopherol (α-TH). In vivo α-TH enrichment of adult hepatic mitochondria increased their MPT resistance. Tetra-linoleoyl cardiolipin (TL-CL), the primary molecular species of CL, was reduced in mitochondria of the young rat; however, enrichment with CL and TL-CL only modestly increased their MPT susceptibility. In conclusion, we observed an unexpected resistance in young rats to bile acid induction of mitochondrial cell death pathways, which may be related to developmental differences in membrane composition.
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Abbreviations
- α-TH:
-
alpha-tocopherol
- α-TTP:
-
alpha-tocopherol transfer protein
- CL:
-
cardiolipin
- GSH-Px:
-
glutathione peroxidase
- GSSG-R:
-
glutathione reductase
- GCDC:
-
glycochenodeoxycholic acid
- MPT:
-
mitochondrial permeability transition
- ROS:
-
reactive oxygen species
- TL-CL:
-
tetra-linoleoyl CL
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Supported in part by grants to RJS from the NIH (RO1DK038446); The Children's Hospital Research Institute and the Abby Bennet Liver Research Fund, and grants to MGT from the NIH (RO1DK59576) and the Environmental Health Sciences Center at Oregon State University (NIEHS P30 ES00210).Presented in part at the 56th Annual Meeting of the American Association for the Study of Liver Diseases, San Francisco, CA, November 2005, and published in abstract form (Hepatology 2005; 777A); and at the 58th Annual Meeting of the American Association for the Study of Liver Diseases, Boston, MA, November 2007 and published in abstract form (Hepatology 2007: 516 A).Supplemental materials, which accompany this article, are available online at http://www.pedresearch.org
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Gumpricht, E., Devereaux, M., Dahl, R. et al. Resistance of Young Rat Hepatic Mitochondria to Bile Acid-Induced Permeability Transition: Potential Role of α-Tocopherol. Pediatr Res 64, 498–504 (2008). https://doi.org/10.1203/PDR.0b013e3181841ee1
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DOI: https://doi.org/10.1203/PDR.0b013e3181841ee1
