Increased Susceptibility of Striatal Mitochondria to Calcium-Induced Permeability Transition

Abstract

Mitochondria were simultaneously isolated from striatum and cortex of adult rats and compared in functional assays for their sensitivity to calcium activation of the permeability transition. Striatal mitochondria showed an increased dose-dependent sensitivity to Ca2+ compared with cortical mitochondria, as measured by mitochondrial depolarization, swelling, Ca2+ uptake, reactive oxygen species production, and respiration. Ratios of ATP to ADP were lower in striatal mitochondria exposed to calcium despite equal amounts of ADP and ATP under respiring and nonrespiring conditions. The Ca2+-induced changes were inhibited by cyclosporin A or ADP. These responses are consistent with Ca2+ activation of both low and high permeability pathways constituting the mitochondrial permeability transition. In addition to the striatal supersensitivity to induction of the permeability transition, cyclosporin A inhibition was less potent in striatal mitochondria. Immunoblots indicated that striatal mitochondria contained more cyclophilin D than cortical mitochondria. Thus striatal mitochondria may be selectively vulnerable to the permeability transition. Subsequent mitochondrial dysfunction could contribute to the initial toxicity of striatal neurons in Huntington's disease.

Calcium-induced generation of reactive oxygen species in brain mitochondria is mediated by permeability transition

“…This enabled evaluation of a wide range of mPT inhibition by the cyclosporin analogs. Analogs 1-15 (identity given in Table 1) were evaluated in both mouse brain and mouse liver mitochondria, analogs [16][17][18][19] in mouse liver mitochondria only and NIM811 and UNIL025 (renamed DEBIO-025) were evaluated previously in rat brain mitochondria [28]. To enable inter-experimental comparisons of all analogs their relative inhibition of calcium-induced mPT was compared to that of CsA, all at 1 µM.…”

“…Increased ROS production from mitochondria has been demonstrated following NMDA receptor stimulation in models of excitotoxicity and has also been coupled to mitochondrial loading of calcium [10][11][12][13][14][15]. However, the mechanism linking mitochondrial calcium loading and ROS production is currently unresolved [15][16][17], and studies in isolated brain mitochondria have yielded diverging results regarding the effect of calcium on mitochondrial ROS generation [18][19][20][21][22]. Mitochondria are able to buffer cellular calcium transients and have high capacity for calcium retention under normal physiological conditions [23].…”

Age‐related changes in regional brain mitochondria from Fischer 344 rats

“…Next, we sought to verify that striatal mitochondria from Fischer 344 rats were more sensitive to Ca 2+ activation of the permeability transition than cortical mitochondria, as in SpragueDawley rats (Brustovetsky et al ., 2003). Changes in mitochondrial membrane potential and mitochondrial swelling, indicative of mPT induction, were assessed by following changes in TPP + accumulation and light scattering, respectively.…”

“…-induced depolarization and swelling is prevented by pretreatment with mPT antagonists, cyclosporine A or a combination of ADP and oligomycin (Crompton & Andreeva, 1994;Brustovetsky & Dubinsky, 2000a,b;Brustovetsky et al ., 2002Brustovetsky et al ., , 2003Brustovetsky et al ., , 2005. In response to Ca 2+ , striatal and cortical mitochondria from adult Fischer 344 rats were differentially sensitive to Ca 2+ induction of the mPT (Fig.…”

“…Depolarized mitochondrial membrane potential by itself would reduce the driving force for Ca 2+ entry and could possibly lessen the mitochondrial contribution to clearance of cytosolic Ca 2+ loads. Previously, we reported that striatal mitochondria were more sensitive to Ca 2+ activation of the mPT than cortical mitochondria (Brustovetsky et al ., 2003). These studies used both male and female Sprague-Dawley rats of 250 g. However, advancing age is a major factor in the onset and progression of a number of neurodegenerative diseases.…”