Mitochondria are responsible for the production of >90% of mammalian cell energy and are intimately linked to the apoptosis signaling cascade. They have critical functions specific to certain tissues including involvement in hemoglobin synthesis, estrogen and testosterone production, and cholesterol metabolism.
There are several mechanisms by which chemical compounds can adversely affect mitochondria. Mitochondrial DNA (mtDNA) replication can be disrupted, as with the case of drugs like AZT that inhibit reverse transcriptase of retroviruses. Some compounds can directly inhibit the electron transport chain or uncouple ATP synthesis from electron transport. Other compounds can inhibit the Krebs cycle, affect mitochondrial membrane permeability or inhibit mitochondrial transporters.
In spite of the critical roles that mitochondria play in all cells, mitochondrial toxicity is difficult to identify. Many of the cell lines used in high-throughput drug discovery screens are highly proliferative, immortalized cell lines that, in the presence of glucose, use glycolysis for energy production, despite abundant oxygen and functional mitochondria, a phenomenon known as the Crabtree effect. As a result these cells tend to be resistant to compounds that disrupt mitochondrial oxidative respiration.
Almost all cells can tolerate diminished mitochondrial membrane potential as long as minimal capacity is maintained; however, when that minimal capacity is lost, cells die rapidly via apoptosis or necrosis, and mitochondrial toxicity is not often identified as the underlying cause of cell death. Often with mitochondrial toxicity there is a lack of correlation between drug dose and toxicity, and toxicity can be missed in clinical trials because it is often highly dependent on individual genetics and organ history.