ArticleThe Journal of biological chemistry2008
Impaired regulation of brain mitochondria by extramitochondrial Ca2+ in transgenic Huntington disease rats.
Article in The Journal of biological chemistry, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.
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Who cites it
40 citing papers in PubMed, 85 citations in OpenAlex.
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- Calcium-Dependent Interaction of Nitric Oxide Synthase with CytochromeBrain sciences · 2023Article
- HSF1 and Its Role in Huntington's Disease Pathology.Advances in experimental medicine and biology · 2023Review
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- Excitotoxicity, calcium and mitochondria: a triad in synaptic neurodegeneration.Translational neurodegeneration · 2022Review
- Power Failure of Mitochondria and Oxidative Stress in Neurodegeneration and Its Computational Models.Antioxidants (Basel, Switzerland) · 2021Review
- Oxygen Consumption Evaluation: An Important Indicator of Metabolic State, Cellular Function, and Cell Fate Along Neural Deregulation.Methods in molecular biology (Clifton, N.J.) · 2021Article
- Calcium-Handling Defects and Neurodegenerative Disease.Cold Spring Harbor perspectives in biology · 2020Review
- Cytosolic, but not matrix, calcium is essential for adjustment of mitochondrial pyruvate supply.The Journal of biological chemistry · 2020Article
- Biological Aging and the Cellular Pathogenesis of Huntington's Disease.Journal of Huntington's disease · 2020Review
- Mutant huntingtin fails to directly impair brain mitochondria.Journal of neurochemistry · 2019Article
- Exercise and metformin counteract altered mitochondrial function in the insulin-resistant brain.JCI insight · 2019Article
- Insulin deficiency and intranasal insulin alter brain mitochondrial function: a potential factor for dementia in diabetes.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2019Article
- Development and Application of Sub-Mitochondrial Targeted CaFrontiers in cellular neuroscience · 2019Article
- Oxidative metabolism and CaNeurochemistry international · 2017Article
- The chicken or the egg: mitochondrial dysfunction as a cause or consequence of toxicity in Huntington's disease.Mechanisms of ageing and development · 2017Review
- Towards an Understanding of Energy Impairment in Huntington's Disease Brain.Journal of Huntington's disease · 2017Review
- Activation of Mitochondrial Complex II-Dependent Respiration Is Beneficial for α-Synucleinopathies.Molecular neurobiology · 2016Article
- Mutant Huntingtin and Elusive Defects in Oxidative Metabolism and Mitochondrial Calcium Handling.Molecular neurobiology · 2016Review
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Authors and funding
11 authors at 8 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
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.
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