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
Source: PubMed


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.

    • "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). "
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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). "
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