Calcium Handling by Endoplasmic Reticulum and Mitochondria in a Cell Model of Huntington ’s Disease

DISCUSSION The involvement of mitochondrial defects in the molecular aetiology of HD was suggested for the first time more than ten years ago, based on the evidence that 3-NPA, an inhibitor of complex II of the respiratory chain, was per se able to induce Htt-like symptoms14,45,46. A number of reports have then described defects in the morphology of mitochondria in HD model cells15,19,47,48,49. Impaired respiratory chain activity50,51 and abnormalities of mitochondrial Ca2+ handling have been described in most of the experimental HD models currently in use9,41,52, reinforcing the idea of a role for mitochondrial defects and Ca2+ dyshomeostasis in the development of the disease. Opinions on the topic are divergent: some studies have claimed that mitochondria from HD model cells have increased propensity to depolarize and are more susceptible to Ca2+ overload, i.e. to the induction of the permeability transition (PTP)33,53,54. Other studies have reported opposite results, concluding that mHtt would instead lower the probability of PTP opening55,56. These discrepancies could be due to the use of isolated mitochondria, removed from the influence of the physiological context of intact cells, or to the use of stable cell lines which could develop adaptive mechanisms to compensate for the derangement of specific intracellular processes17,41. However, experimental outcomes obtained in primary striatal neurons carrying a pathogenic mHtt with 128Q show that PTP inhibitors significa...
Source: PLOS Currents Huntington Disease - Category: Neurology Authors: Source Type: research