Mitochondrial function in Huntington’s disease: a comparison between isolated and in-situ mitochondria

• Type: International Conference Proceedings Book
• Date: 2005

Authors

Jorge M.A. Oliveira (Author) FFUP; Jekabsons MB (Author) Other; Chen S (Author) Other; Riley R (Author) Other; Lin A (Author) Other; Ellerby LM (Author) Other; Rego AC (Author) Other; NIcholls DG (Author) Other

Publisher

Journal of Neurology, Neurosurgery and Psychiatry

Conference International

HDA meeting: World Congress on Huntington's disease

Manchester, UK, 2005

Scientific classification

FOS: Medical and Health sciences > Health sciences

CORDIS: Health sciences > Pharmacological sciences ; Health sciences > Neuroscience > Neurochemistry ; Health sciences > Neuroscience > Neurophysiology

Other information

Resumo (PT): Mitochondrial dysfunction and excitotoxicity are believed to play an important role in the pathology of Huntington's disease (HD). This hereditary CAG-triplet repeat disorder has 100% of penetrance and selectively targets striatal neurons, invariably progressing to motor abnormalities, dementia and death. The development of animal models that accurately recapitulate HD is of utmost importance for the development of treatment strategies. In the present study we compared isolated forebrain mitochondria from different transgenic HD mice (R6/2, YAC128 and Hdh-CAG150). Maximal calcium-loading capacity (MCLC) of state 4 mitochondria was similar for all wild-type controls despite the different genetic backgrounds. Interestingly, MCLC was increased in R6/2 and YAC128 mice whereas no differences were found in Hdh-CAG150 mice. In order to assess mitochondrial function in intact neurons, we prepared primary striatal cultures from YAC128, Hdh-CAG150 and respective wild-type littermates. Changes in mitochondrial membrane potential and intracellular calcium were monitored in single cells by fluorescence microscopy. Oxygen consumption by neuronal populations was monitored using a previously described respirometer (Jekabsons and Nicholls, JBC, 2004). Striatal neurons from HD mice presented a decreased maximal respiratory capacity and NMDA challenging resulted in mitochondrial depolarization in association with delayed recovery of basal calcium. These results highly suggested mitochondrial dysfunction in HD striatal neurons. Conflicting results with experiments using isolated mitochondria may derive from: (i) mitochondria isolation from a mixed forebrain neuronal population, masking HD selective striatal pathology; and/or (ii) loss of interaction with soluble cytoplasmic htt in isolated mitochondria. These results stress the importance of addressing mitochondrial function in the cellular context. Acknowledgements: High-Q Foundation (USA) and Calouste Gulbenkian Foundation (PT)

Abstract (EN): Mitochondrial dysfunction and excitotoxicity are believed to play an important role in the pathology of Huntington's disease (HD). This hereditary CAG-triplet repeat disorder has 100% of penetrance and selectively targets striatal neurons, invariably progressing to motor abnormalities, dementia and death. The development of animal models that accurately recapitulate HD is of utmost importance for the development of treatment strategies. In the present study we compared isolated forebrain mitochondria from different transgenic HD mice (R6/2, YAC128 and Hdh-CAG150). Maximal calcium-loading capacity (MCLC) of state 4 mitochondria was similar for all wild-type controls despite the different genetic backgrounds. Interestingly, MCLC was increased in R6/2 and YAC128 mice whereas no differences were found in Hdh-CAG150 mice. In order to assess mitochondrial function in intact neurons, we prepared primary striatal cultures from YAC128, Hdh-CAG150 and respective wild-type littermates. Changes in mitochondrial membrane potential and intracellular calcium were monitored in single cells by fluorescence microscopy. Oxygen consumption by neuronal populations was monitored using a previously described respirometer (Jekabsons and Nicholls, JBC, 2004). Striatal neurons from HD mice presented a decreased maximal respiratory capacity and NMDA challenging resulted in mitochondrial depolarization in association with delayed recovery of basal calcium. These results highly suggested mitochondrial dysfunction in HD striatal neurons. Conflicting results with experiments using isolated mitochondria may derive from: (i) mitochondria isolation from a mixed forebrain neuronal population, masking HD selective striatal pathology; and/or (ii) loss of interaction with soluble cytoplasmic htt in isolated mitochondria. These results stress the importance of addressing mitochondrial function in the cellular context. Acknowledgements: High-Q Foundation (USA) and Calouste Gulbenkian Foundation (PT)

Language: Portuguese

Type (Professor's evaluation): Scientific