Mitochondria as a Critical Target for Toxicity

Gurmit Singh and Wilhelmina C.M. Duivenvoorden
Hamilton Regional Cancer Centre
699 Concession St.
Hamilton, Ontario, Canada

Mitochondria perform a variety of important cellular functions. In addition to synthesizing ATP by oxidative phosphorylation, they synthesize lipids, heme, amino acids, pyrimidines and are involved in regulating intracellular pH and ion homeostasis. During the last two decades, mitochondrial DNA (mtDNA) from a number of species has been sequenced. The organelle DNA has been used to exploit the evolutionary aspects of the origin of mitochondria. The endosymbiotic bacterial ancestry suggests that some of the functions fundamental to bacterial life may be retained in mitochondria. Thus, an understanding of both bacterial genes and bacterial function form a basis for identifying novel mitochondrial functions.

There is direct evidence that mtDNA is 5- to 500-fold more sensitive than nuclear DNA to damage induced by several chemicals, with the highest differential relating to polycyclic aromatic hydrocarbons. Damage to mtDNA contributes to the cytotoxic, mutagenic and carcinogenic potential of several drugs and environmental chemicals into reactive electrophilic metabolites, especially since metabolic activation of xenobiotic compounds can occur within or at the surface of mitochondria. Furthermore, the lack of protective histones or non-histone proteins, the limited DNA repair capacity and the attachment of mtDNA to the inner membrane make the mtDNA more susceptible to damage by electrophilic compounds such as peroxides, epoxides, N-nitroso compounds, nitroxides, semiquinones, etc. Some of these electrophiles may be a result of increased metabolic activity in cell induced by hormones, neurotransmitters, etc. Damage to organelle DNA could result in a change in mitochondrial function resulting in alterations in cellular functions, which may manifest as a toxic event in the tissue.

The electrochemical gradient in mitochondria consists of two components, namely a pH gradient and a membrane potential. The two mechanisms that generate an electrochemical gradient are: (1) active pumping of protons across the membrane and (2) the movement of the protons coupled to electron transfer. The magnitude of the mitochondrial membrane potential differs depending on the cell type. The mitochondrial membrane potential in cells from different tissues from highest to lowest is as follows; cardiac muscle cells > skeletal muscle cells > smooth muscle cells > macrophages > hepatocytes > fibroblasts > neuronal cells > keratinocytes > bladder epithelial cells > resting T and B lymphocytes. Significance of the cell-specific characteristics of mitochondria are poorly understood. However, tissue-specific toxicities could be related to the electrochemical gradient within mitochondria of various tissues. In certain instances, the dissipation of the gradient could result in altered cellular function or could initiate damage of the vulnerable genome resulting in toxic cellular effects. Damage to mitochondria by various drugs and toxicants has been well established and good morphological data has been available for a very long time.

In conclusion, various chemicals can disrupt mitochondrial functions via disruption of the electrochemical gradient or damage to the mtDNA resulting in cellular toxicity.

(This work is supported by the Medical Research Council of Canada to G. Singh)