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Evidence suggests that neuronal dysfunction in Huntington's disease (HD) striatum involves deficits in mitochondrial function and in Ca2+ handling. However, the relationship between mitochondria and Ca2+ handling has been incompletely studied in intact HD striatal cells. Treatment with histone deacetylase (HDAC) inhibitors reduces cell death in HD models, but the effects of this promising therapy on cellular function are mostly unknown. Here, we use real-time functional imaging of intracellular Ca2+ and mitochondrial membrane potential to explore the role of in situ HD mitochondria in Ca2+ handling. Immortalized striatal (STHdh) cells and striatal neurons from transgenic mice, expressing full-length mutant huntingtin (Htt), were used to model HD. We show that (1) active glycolysis in STHdh cells occludes the mitochondrial role in Ca2+ handling as well as the effects of mitochondrial inhibitors, (2) STHdh cells and striatal neurons in the absence of glycolysis are critically dependent on oxidative phosphorylation for energy-dependent Ca2+ handling, (3) expression of full-length mutant Htt is associated with deficits in mitochondrial-dependent Ca2+ handling that can be ameliorated by treatment with HDAC inhibitors (treatment with trichostatin A or sodium butyrate decreases the proportion of STHdh cells losing Ca2+ homeostasis after Ca2+-ionophore challenging, and accelerates the restoration of intracellular Ca2+ in striatal neurons challenged with NMDA), and (4) neurons with different response patterns to NMDA receptor activation exhibit different average somatic areas and are differentially affected by treatment with HDAC inhibitors, suggesting subpopulation or functional state specificity. These findings indicate that neuroprotection induced by HDAC inhibitors involves more efficient Ca2+ handling, thus improving the neuronal ability to cope with excitotoxic stimuli.

Mitochondrial-Dependent Ca2+Handling in Huntington's Disease Striatal Cells: Effect of Histone Deacetylase Inhibitors

Mitochondrial-Dependent Ca²⁺Handling in Huntington's Disease Striatal Cells: Effect of Histone Deacetylase Inhibitors