title: Mitochondrial cristae remodelling is associated with disrupted OPA1 oligomerisation in the Huntington's disease R6/2 fragment model.
abstract: There is evidence of an imbalance of mitochondrial fission and fusion in patients with Huntington's disease (HD) and HD animal models. Fission and fusion are important for mitochondrial homeostasis including mitochondrial DNA (mtDNA) maintenance and may be relevant for the selective striatal mtDNA depletion that we observed in the R6/2 fragment HD mouse model. We aimed to investigate the fission/fusion balance and the integrity of the mitochondrial membrane system in cortex and striatum of end-stage R6/2 mice and wild-type animals. Mitochondrial morphology was determined using electron microscopy, and transcript and protein levels of factors that play a key role in fission and fusion, including DRP1, mitofusin 1 and 2, mitofilin and OPA1, and cytochrome c and caspase 3 were assessed by RT-qPCR and immunoblotting. OPA1 oligomerisation was evaluated using blue native gels. In striatum and cortex of R6/2 mice, mitochondrial cristae morphology was abnormal. Mitofilin and the overall levels of the fission and fusion factors were unaffected; however, OPA1 oligomerisation was abnormal in striatum and cortex of R6/2 mice. Mitochondrial and cytoplasmic cytochrome c levels were similar in R6/2 and wild-type mice with no significant increase of activated caspase 3. Our results indicate that the integrity of the mitochondrial cristae is compromised in striatum and cortex of the R6/2 mice and that this is most likely caused by impaired OPA1 oligomerisation.
authors.affiliation: Department of Neurology, Ulm University, Germany.
authors.forename: Tanja
authors.initials: T
authors.lastname: Hering
authors.affiliation: Department of Neurology, Ulm University, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Kojer
authors.affiliation: Department of Neurology, Ulm University, Germany.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Birth
authors.affiliation: Department of Neurology, Ulm University, Germany.
authors.forename: Jaqueline
authors.initials: J
authors.lastname: Hallitsch
authors.affiliation: Department of Clinical Neurosciences, Institute of Neurology, University College London, London, UK.
authors.forename: Jan-Willem
authors.initials: JW
authors.lastname: Taanman
authors.affiliation: Department of Neurology, Ulm University, Germany. Electronic address: michael.orth@uni-ulm.de.
authors.forename: Michael
authors.initials: M
authors.lastname: Orth
mesh_terms: D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D002540:Cerebral Cortex / Q000648:ultrastructure*; D003342:Corpus Striatum / Q000648:ultrastructure*; D045304:Cytochromes c / Q000235:genetics / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000378:metabolism; D004195:Disease Models, Animal; D034281:Dynamins / Q000235:genetics / Q000378:metabolism; D042967:Electron Transport Complex I / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism*; D000071058:Huntingtin Protein / Q000235:genetics; D006816:Huntington Disease / Q000235:genetics / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism* / Q000648:ultrastructure; D063154:Mitochondrial Dynamics / Q000235:genetics; D018911:Trinucleotide Repeats / Q000235:genetics
chemical_list: D004272:DNA, Mitochondrial; C086055:HTT protein, human; D000071058:Huntingtin Protein; D045304:Cytochromes c; D053148:Caspase 3; D020558:GTP Phosphohydrolases; C488750:Mfn1 protein, mouse; C488751:Mfn2 protein, mouse; C498809:Opa1 protein, mouse; C486391:Dnm1l protein, mouse; D034281:Dynamins; D042967:Electron Transport Complex I; C571164:NDUFA9 protein, human
keywords: Caspase 3; Cristae integrity; Fission and fusion; Mitofilin; OPA 1 oligomerisation