Browsing by Author "Jin, Youngnam N."

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    Mitochondrial permeability transition pore induces mitochondria injury in Huntington disease
    (2013) Quintanilla, Rodrigo A.; Jin, Youngnam N.; Bernhardi Montgomery, Rommy von; Johnson, Gail V.
    Abstract Background Mitochondrial impairment has been implicated in the pathogenesis of Huntington’s disease (HD). However, how mutant huntingtin impairs mitochondrial function and thus contributes to HD has not been fully elucidated. In this study, we used striatal cells expressing wild type (STHdhQ7/Q7) or mutant (STHdhQ111/Q111) huntingtin protein, and cortical neurons expressing the exon 1 of the huntingtin protein with physiological or pathological polyglutamine domains, to examine the interrelationship among specific mitochondrial functions. Results Depolarization induced by KCl resulted in similar changes in calcium levels without compromising mitochondrial function, both in wild type and mutant cells. However, treatment of mutant cells with thapsigargin (a SERCA antagonist that raises cytosolic calcium levels), resulted in a pronounced decrease in mitochondrial calcium uptake, increased production of reactive oxygen species (ROS), mitochondrial depolarization and fragmentation, and cell viability loss. The mitochondrial dysfunction in mutant cells was also observed in cortical neurons expressing exon 1 of the huntingtin protein with 104 Gln residues (Q104-GFP) when they were exposed to calcium stress. In addition, calcium overload induced opening of the mitochondrial permeability transition pore (mPTP) in mutant striatal cells. The mitochondrial impairment observed in mutant cells and cortical neurons expressing Q104-GFP was prevented by pre-treatment with cyclosporine A (CsA) but not by FK506 (an inhibitor of calcineurin), indicating a potential role for mPTP opening in the mitochondrial dysfunction induced by calcium stress in mutant huntingtin cells. Conclusions Expression of mutant huntingtin alters mitochondrial and cell viability through mPTP opening in striatal cells and cortical neurons.
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    Rosiglitazone treatment prevents mitochondrial dysfunction in mutant huntingtin-expressing cells -: Possible role of peroxisome proliferator-activated receptor-γ (PPARγ) in the pathogenesis of Huntington disease
    (2008) Quintanilla, Rodrigo A.; Jin, Youngnam N.; Fuenzalida, Karen; Bronfman, Miguel; Johnson, Gail V. W.
    Peroxisome proliferator-activated receptor-gamma (PPAR gamma) is a member of the PPAR family of transcription factors. Synthetic PPAR gamma agonists are used as oral anti-hyperglycemic drugs for the treatment of non-insulin-dependent diabetes. However, emerging evidence indicates that PPAR gamma activators can also prevent or attenuate neurodegeneration. Given these previous findings, the focus of this report is on the potential neuroprotective role of PPAR gamma activation in preventing the loss of mitochondrial function in Huntington disease (HD). For these studies we used striatal cells that express wild-type (STHdh(Q7/Q7)) or mutant (STHdh(Q111/Q111)) huntingtin protein at physiological levels. Treatment of mutant cells with thapsigargin resulted in a significant decrease in mitochondrial calcium uptake, an increase in reactive oxygen species production, and a significant decrease in mitochondrial membrane potential. PPAR gamma activation by rosiglitazone prevented the mitochondrial dysfunction and oxidative stress that occurred when mutant striatal cells were challenged with pathological increases in calcium. The beneficial effects of rosiglitazone were likely mediated by activation of PPAR gamma, as all protective effects were prevented by the PPAR gamma antagonist GW9662. Additionally, the PPAR gamma signaling pathway was significantly impaired in the mutant striatal cells with decreases in PPAR gamma expression and reduced PPAR gamma transcriptional activity. Treatment with rosiglitazone increased mitochondrial mass levels, suggesting a role for the PPAR gamma pathway in mitochondrial function in striatal cells. Altogether, this evidence indicates that PPAR gamma activation by rosiglitazone attenuates mitochondrial dysfunction in mutant huntingtin-expressing striatal cells, and this could be an important therapeutic avenue to ameliorate the mitochondrial dysfunction that occurs in HD.