Cisplatin Nephrotoxicity Involves Mitochondrial Injury with Impaired Tubular Mitochondrial Enzyme Activity
Department of Pathology, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.Journal of Histochemistry and Cytochemistry (Impact Factor: 1.96). 04/2012; 60(7):521-9. DOI: 10.1369/0022155412446227
Cisplatin is a widely used antineoplastic agent. However, its major limitation is dose-dependent nephrotoxicity whose precise mechanism is poorly understood. Recent studies have suggested that mitochondrial dysfunction in tubular epithelium contributes to cisplatin-induced nephrotoxicity. Here the authors extend those findings by describing the role of an important electron transport chain enzyme, cytochrome c oxidase (COX). Immunohistochemistry for COX 1 protein demonstrated that, in response to cisplatin, expression was mostly maintained in focally damaged tubular epithelium. In contrast, COX enzyme activity in proximal tubules (by light microscopy) was decreased. Ultrastructural analysis of the cortex and outer stripe of the outer medulla showed decreased mitochondrial mass, disruption of cristae, and extensive mitochondrial swelling in proximal tubular epithelium. Functional electron microscopy showed that COX enzyme activity was decreased in the remaining mitochondria in the proximal tubules but maintained in distal tubules. In summary, cisplatin-induced nephrotoxicity is associated with structural and functional damage to the mitochondria. More broadly, using functional electron microscopy to measure mitochondrial enzyme activity may generate mechanistic insights across a spectrum of renal disorders.
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Article: Cisplatin Nephrotoxicity Involves Mitochondrial Injury with Impaired Tubular Mitochondrial Enzyme Activity
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- "Some authors have described a post-translational modulation of the COX activity under stress conditions through phosphorylation or acetylation (Hüttemann et al., 2012; Lee et al., 2010; Menzies et al., 2013). In the same way, other authors have shown that the COX activity is decreased in the kidney cells in CDDP-treated mice, with a mostly maintained COX expression (Zsengellér et al., 2012). These results are in agreement with the fact that in normal conditions dysfunctional mitochondria are removed (Mijaljica et al., 2007), however, in some cancers this process is inhibited and the damaged mitochondria that have accumulated in the cells would create mitochondrial dysfunction and ROS production (Zhang et al., 2007). "
ABSTRACT: Breast cancer is a leading cause of death for women. The estrogen receptors (ERs) ratio is important in the maintenance of mitochondrial redox status, and higher levels of ERβ increases mitochondrial functionality, decreasing ROS production. Our aim was to determine the interaction between the ERα/ERβ ratio and the response to cytotoxic treatments such as cisplatin (CDDP), paclitaxel (PTX) and tamoxifen (TAM). Cell viability, apoptosis, autophagy, ROS production, mitochondrial membrane potential, mitochondrial mass and mitochondrial functionality were analyzed in MCF-7 (high ERα/ERβ ratio) and T47D (low ERα/ERβ ratio) breast cancer cell lines. Cell viability decreased more in MCF-7 when treated with CDDP and PTX. Apoptosis was less activated after cytotoxic treatments in T47D than in MCF-7 cells. Nevertheless, autophagy was increased more in CDDP-treated MCF-7, but less in TAM-treated cells than in T47D. CDDP treatment produced a raise in mitochondrial mass in MCF-7, as well as the citochrome c oxidase (COX) and ATP synthase protein levels, however significantly reduced COX activity. In CDDP-treated cells, the overexpression of ERβ in MCF-7 caused a reduction in apoptosis, autophagy and ROS production, leading to higher cell survival; and the silencing of ERβ in T47D cells promoted the opposite effects. In TAM-treated cells, ERβ-overexpression led to less cell viability by an increment in autophagy; and the partial knockdown of ERβ in T47D triggered an increase in ROS production and apoptosis, leading to cell death. In conclusion, ERβ expression plays an important role in the response of cancer cells to cytotoxic agents, especially for cisplatin treatment. Copyright © 2015. Published by Elsevier Ltd.The international journal of biochemistry & cell biology 07/2015; 66. DOI:10.1016/j.biocel.2015.07.014 · 4.05 Impact Factor
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- "EM was performed by the BIDMC Electron Micrograph Core. Functional COX EM was performed as previously described (Zsengeller et al., 2012). OCRs (pmol/min) were assessed with the use of an XF Flux Analyzer (Seahorse Biosciences). "
ABSTRACT: The transcriptional coactivators PGC-1α and PGC-1β are widely thought to be required for mitochondrial biogenesis and fiber typing in skeletal muscle. Here, we show that mice lacking both PGC-1s in myocytes do indeed have profoundly deficient mitochondrial respiration but, surprisingly, have preserved mitochondrial content, isolated muscle contraction capacity, fiber-type composition, in-cage ambulation, and voluntary running capacity. Most of these findings are recapitulated in cell culture and, thus, are cell autonomous. Functional electron microscopy reveals normal cristae density with decreased cytochrome oxidase activity. These data lead to the following surprising conclusions: (1) PGC-1s are in fact dispensable for baseline muscle function, mitochondrial content, and fiber typing, (2) endurance fatigue at low workloads is not limited by muscle mitochondrial capacity, and (3) mitochondrial content and cristae density can be dissociated from respiratory capacity.Cell Reports 05/2013; 3(5). DOI:10.1016/j.celrep.2013.04.023 · 8.36 Impact Factor
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