title: Proteomic analysis of mitochondria in APOE transgenic mice and in response to an ischemic challenge.
abstract: Apolipoprotein E (APOE)-ɛ4 is associated with a deleterious outcome after ischemic brain injury, which may involve abnormal regulation of mitochondrial function. We have assessed the mitochondrial proteomic response of APOE-ɛ3 and APOE-ɛ4 transgenic mice to transient global ischemic injury in the hippocampus. A genotype-dependent increase in ApoE levels in mitochondria was observed after ischemia, with APOE-ɛ4 mice showing significantly greater increases than APOE-ɛ3 mice. Quantitative analysis of the mitochondria-enriched fractions was performed using liquid-chromatography mass spectrometry coupled to label-free analysis. Of the 1,067 identified proteins, 274 were mitochondria associated. Mitochondrial protein expression was significantly different between genotypes under basal conditions as well as in response to global ischemia. A total of 12 mitochondrial proteins (including respiratory chain proteins NDUFA11, NDUFS3, NDUF5B, ATP5J, as well as ETFA, CYB5B, ATP6V1A, HSPA1B, OXR1, GLUL, IARS2, and PHYHIPL) were significantly altered with respect to genotype, global ischemia, or their interaction (P<0.01). A compelling interactome, created using proteins found to be significantly modulated by global ischemia (P<0.05), involved proteins that regulate energy production and oxidative stress. Thus, APOE genotype has a differential effect on the mitochondrial protein expression in the absence and presence of an injury, which may underlie the differing genotype susceptibility.
authors: Centre for Cognitive Aging and Cognitive Epidemiology, Centre for Cognitive and Neural Systems, School of Biomedical Sciences, University of Edinburgh, Edinburgh, UK.
authors: Rachel
authors: R
authors: James
authors: James L
authors: JL
authors: Searcy
authors: Thierry
authors: T
authors: Le Bihan
authors: Sarah F
authors: SF
authors: Martin
authors: Catherine M
authors: CM
authors: Gliddon
authors: Joanne
authors: J
authors: Povey
authors: Ruth F
authors: RF
authors: Deighton
authors: Lorraine E
authors: LE
authors: Kerr
authors: James
authors: J
authors: McCulloch
authors: Karen
authors: K
authors: Horsburgh
mesh_terms: D000818:Animals; D053318:Apolipoprotein E3 / Q000235:genetics / Q000378:metabolism*; D053327:Apolipoprotein E4 / Q000235:genetics / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D019295:Computational Biology; D004195:Disease Models, Animal; D004591:Electrophoresis, Polyacrylamide Gel; D005838:Genotype; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D015151:Immunoblotting; D002546:Ischemic Attack, Transient / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism*; D016571:Neural Networks, Computer; D018384:Oxidative Stress; D020033:Protein Isoforms; D040901:Proteomics / Q000379:methods*; D053719:Tandem Mass Spectrometry
chemical_list: D053318:Apolipoprotein E3; D053327:Apolipoprotein E4; D024101:Mitochondrial Proteins; D020033:Protein Isoforms