Given the multiple functions and numerous proteins present in the mitochondria, it is not surprising that genetically inherited defects of mitochondrial function are a major cause of morbidity and mortality in humans.ref In particular, there are several human diseases that have known defects in the proteins responsible for oxidative phosphorylation (OxPhos) in cells. Typically, such defects produce lactic acidemia, exercise intolerance or neurological disorders.

Diseases of OxPhos are notoriously difficult to diagnose, and it is even more difficult to correlate their phenotype–genotype relationships. A subset of OxPhos defects is maternally inherited. These defects result from mutations in mitochondrial DNA (mtDNA), a small, 16-kb genome present in hundreds to thousands of copies per cell.ref mtDNA, which encodes 13 polypeptides of the OxPhos machinery, differs from the nuclear genome in its absence of histones, poor repair mechanisms and very limited recombination frequencies. As a result, mtDNA in somatic cells builds up mutations over time due to errors in replication that are not repaired and physical insult from a variety of toxins.ref Such accumulated mutations are implicated in a number of neurodegenerative diseases ref—notably Parkinson disease and Alzheimer disease—where the mutation load triggers premature apoptotic or necrotic cell death. For example, a strong link has been established between exposure to the pesticide rotenone, a well-defined and specific inhibitor of OxPhos, and Parkinson disease. mtDNA mutations function by reducing energy production within the cell and are thought to contribute to cancer and aging. Likewise, mutations in the nuclear-encoded subunits of OxPhos have been found to regulate the life span in flies and worms. Many of the products listed in this section are useful tools for studying degenerative conditions.ref