title: Resistance of young rat hepatic mitochondria to bile acid-induced permeability transition: potential role of alpha-tocopherol.
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 alpha-tocopherol (alpha-TH). In vivo alpha-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.
authors.affiliation: Department of Pediatrics, University of Colorado Denver School of Medicine, Aurora, Colorado 80045, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Gumpricht
authors.forename: Michael W
authors.initials: MW
authors.lastname: Devereaux
authors.forename: Rolf
authors.initials: R
authors.lastname: Dahl
authors.forename: Jason S
authors.initials: JS
authors.lastname: Soden
authors.forename: Genevieve C
authors.initials: GC
authors.lastname: Sparagna
authors.forename: Scott W
authors.initials: SW
authors.lastname: Leonard
authors.forename: Maret G
authors.initials: MG
authors.lastname: Traber
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Sokol
mesh_terms: D000367:Age Factors; D000818:Animals; D002308:Cardiolipins / Q000378:metabolism; D016923:Cell Death; D045304:Cytochromes c / Q000378:metabolism; D005999:Glycochenodeoxycholic Acid / Q000378:metabolism*; D008930:Mitochondria, Liver / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000378:metabolism*; D000083162:Mitochondrial Permeability Transition Pore; D010084:Oxidation-Reduction; D051381:Rats; D024502:alpha-Tocopherol / Q000378:metabolism*
chemical_list: D002308:Cardiolipins; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D005999:Glycochenodeoxycholic Acid; D045304:Cytochromes c; D024502:alpha-Tocopherol