Cisplatin Nephrotoxicity Involves Mitochondrial Injury with Impaired Tubular Mitochondrial Enzyme Activity

Zsuzsanna K. Zsengellér, Lena Ellezian, Dan Brown, Béla Horváth, Partha Mukhopadhyay, Balaraman Kalyanaraman, Samir M. Parikh, S. Ananth Karumanchi, Isaac E. Stillman, Pál Pacher

Research output: Contribution to journalArticlepeer-review

79 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)521-529
Number of pages9
JournalJournal of Histochemistry and Cytochemistry
Volume60
Issue number7
DOIs
StatePublished - Jul 2012
Externally publishedYes

Keywords

  • cisplatin
  • cytochrome c oxidase
  • functional electron microscopy
  • mitochondria
  • nephrotoxicity

ASJC Scopus subject areas

  • Anatomy
  • Histology

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