title: Impaired regulation of brain mitochondria by extramitochondrial Ca2+ in transgenic Huntington disease rats.
abstract: Huntington disease (HD) is characterized by polyglutamine expansions of huntingtin (htt), but the underlying pathomechanisms have remained unclear. We studied brain mitochondria of transgenic HD rats with 51 glutamine repeats (htt(51Q)), modeling the adult form of HD. Ca(free)(2+) up to 2 mum activated state 3 respiration of wild type mitochondria with glutamate/malate or pyruvate/malate as substrates. Ca(free)(2+) above 2 mum inhibited respiration via cyclosporin A-dependent permeability transition (PT). Ruthenium red, an inhibitor of the mitochondrial Ca(2+) uniporter, did not affect the Ca(2+)-dependent activation of respiration but reduced Ca(2+)-induced inhibition. Thus, Ca(2+) activation was mediated exclusively by extramitochondrial Ca(2+), whereas inhibition was promoted also by intramitochondrial Ca(2+). In contrast, htt(51Q) mitochondria showed a deficient state 3 respiration, a lower sensitivity to Ca(2+) activation, and a higher susceptibility to Ca(2+)-dependent inhibition. Furthermore htt(51Q) mitochondria exhibited a diminished membrane potential stability in response to Ca(2+), lower capacities and rates of Ca(2+) accumulation, and a decreased Ca(2+) threshold for PT in a substrate-independent but cyclosporin A-sensitive manner. Compared with wild type, Ca(2+)-induced inhibition of respiration of htt(51Q) mitochondria was less sensitive to ruthenium red, indicating the involvement of extramitochondrial Ca(2+). In conclusion, we demonstrate a novel mechanism of mitochondrial regulation by extramitochondrial Ca(2+). We suggest that specific regulatory Ca(2+) binding sites on the mitochondrial surface, e.g. the glutamate/aspartate carrier (aralar), mediate this regulation. Interactions between htt(51Q) and distinct targets such as aralar and/or the PT pore may underlie mitochondrial dysregulation leading to energetic depression, cell death, and tissue atrophy in HD.
authors.affiliation: KeyNeurotek Pharmaceuticals AG, ZENIT Technology Park, 39120 Magdeburg, Germany. frank.gellerich@keyneurotek.de
authors.forename: Frank N
authors.initials: FN
authors.lastname: Gellerich
authors.forename: Zemfira
authors.initials: Z
authors.lastname: Gizatullina
authors.forename: Huu P
authors.initials: HP
authors.lastname: Nguyen
authors.forename: Sonata
authors.initials: S
authors.lastname: Trumbeckaite
authors.forename: Stefan
authors.initials: S
authors.lastname: Vielhaber
authors.forename: Enn
authors.initials: E
authors.lastname: Seppet
authors.forename: Stephan
authors.initials: S
authors.lastname: Zierz
authors.forename: Bernhard
authors.initials: B
authors.lastname: Landwehrmeyer
authors.forename: Olaf
authors.initials: O
authors.lastname: Riess
authors.forename: Stephan
authors.initials: S
authors.lastname: von Hörsten
authors.forename: Frank
authors.initials: F
authors.lastname: Striggow
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D002118:Calcium / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D004396:Coloring Agents / Q000494:pharmacology; D016572:Cyclosporine / Q000494:pharmacology; D004734:Energy Metabolism / Q000187:drug effects / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000235:genetics; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010101:Oxygen Consumption / Q000187:drug effects / Q000235:genetics; D051381:Rats; D055647:Rats, Transgenic; D012430:Ruthenium Red / Q000494:pharmacology
chemical_list: D004396:Coloring Agents; D004791:Enzyme Inhibitors; C499524:Htt protein, rat; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D012430:Ruthenium Red; D016572:Cyclosporine; D002118:Calcium