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Introduction to Mitochondrial Toxicity

Molecular and Cellular Aspects of Toxicology

  1. Yvonne Will PhD1,
  2. James A. Dykens PhD2

Published Online: 15 DEC 2009

DOI: 10.1002/9780470744307.gat021

General, Applied and Systems Toxicology

General, Applied and Systems Toxicology

How to Cite

Will, Y. and Dykens, J. A. 2009. Introduction to Mitochondrial Toxicity. General, Applied and Systems Toxicology. .

Author Information

  1. 1

    Pfizer R&D, Compound Safety Prediction-Cellular Toxicology, World Wide Medicinal Chemistry, Groton, USA

  2. 2

    Pfizer Inc, Drug Safety R&D, IPC 699, Sandwich, Kent, UK

Publication History

  1. Published Online: 15 DEC 2009


Mitochondria generate >90% of the energy in aerobically poised cells, but are also a major source of cytotoxic free radicals. These organelles contain their own genome, and they replicate independent of cell division. It is widely appreciated that chronic exposures to some antibacterial and antiviral drugs can interfere with mitochondrial gene expression and/or replication, leading to various toxicities, including hearing loss, lipodystrophy and lipoatrophies. It is now increasingly appreciated that xenobiotics also can directly undermine mitochondrial function on more acute time scales, either by inhibiting respiration, or by uncoupling electron transport from phosphorylation, and in some cases, by both mechanisms. Such drug-induced mitochondrial dysfunction varies across important classes of therapeutics, and potency is in accord with clinical disposition; compounds that most profoundly impair mitochondrial function have been withdrawn from the market, or dropped before the clinic because of various organ toxicities. Examples of drugs with known mitochondrial liabilities are discussed, especially in the context of modern drug development. Such drug toxicity was not widely detected because of inadequacies in typical cell-based and in vitro assays, but new, high throughput assays have been designed to reveal mitochondrial impairment earlier in drug development. Drug-induced organ toxicity is a function organ history and physiological scope, i.e., the bioenergetic and antioxidative reserve capacity that has to be eroded before crossing a threshold of toxicity. This threshold model supports a new model of idiosyncratic drug toxicity that also incorporates all the known risk factors for such a response.


  • mitochondria;
  • mitochondrial transcription and translation;
  • xidative phosphorylation;
  • calcium homeostasis;
  • uncoupling/inhibition;
  • mitochondrial permeability transition;
  • drug-induced toxicities;
  • idiosyncratic drug reactions;
  • methods to investigate mitochondrial dysfunction