The Greek myth of the giant Prometheus stealing fire from the Olympian gods and giving it to humans, and the gods’ “Trojan horse” gift to Prometheus of the beautiful but incorrigibly curious Pandora neatly symbolizes the symbiotic origin of mitochondrial DNA (mtDNA) and its role in human health and pathology (including aging).

I will review our relatively recent awareness of mtDNA and our even more recent discovery of its important role in human pathology. The first two pathogenic mutations in mtDNA were reported in 1988: 24 years later, over 200 point mutations and innumerable deletions have been associated with an extraordinary variety of human disorders, most of them multisystemic (“mitochondrial encephalomyopathies”) but some tissue-specific (for example, mitochondrial myopathies). After a brief reminder of the unique rules of mitochondrial genetics, I will propose a genetic classification of the mitochondrial disorders and provide examples of different mtDNA-related diseases. As a myologist by training, I feel obliged to stress the importance of the muscle biopsy in our diagnostic approach to mitochondrial diseases. As mtDNA mutations are so common, it is important to recognize which are pathogenic and which are neutral polymorphisms. I will, therefore, review and provide examples of the “canonical” criteria of mtDNA pathogenicity, including heteroplasmy, single fiber PCR, and the cybrid technology.

In 2000, I wrote a review titled “Mutations in mtDNA: are we scraping the bottom of the barrel?” (Brain Pathology 2000:10:431-441). I will proceed to show that we are far from scratching the bottom of the barrel. We are still debating the frequency of mtDNA-related disorders; novel mutations or novel clinical phenotypes are still being reported at a brisk pace; the role of homoplasmic pathogenic mutations is not yet fully understood; similarly, the modulating role of mtDNA haplotypes is still being described; and – importantly – the pathogenic mechanism of mtDNA mutations is not yet understood (in other words, we still do not understand why MELAS differs from MERRF when both syndromes are due to mutations in mtDNA tRNA genes). It has been aptly said that mtDNA is the slave of nuclear DNA (nDNA), in that, in the course of the millennia, mtDNA has lost most of its original autonomy and now depends heavily on nuclear DNA for its basic functions, including replication and maintenance. Thus, besides disorders (reviewed above) due to “primary” mtDNA mutations, there are many disorders due to mutations in nuclear genes controlling mtDNA replication (mtDNA depletion syndromes), mtDNA maintenance (multiple mtDNA deletions syndromes) or mtDNA translation. These “indirect hits” (defects of intergenomic communication) are transmitted as mendelian traits but have genetic features that overlap with mitochondrial genetics. Thanks to new generation mitoexome sequencing, the neat subdivision between mtDNA depletion and multiple mtDNA syndromes is crumbling, as mutations in the same genes (usually involved with the homeostasis of the mitochondrial nucleotide pool) can impair either mtDNA replication or maintenance (or both).

In a provocative article, the late Anita Harding wondered whether normal aging wasn’t the most common mitochondrial disease of them all. There is considerable evidence that this is true and largely due to spontaneous accumulations of mtDNA deletions in postmitotic tissues.

Finally, although I don’t have the time to review therapeutic strategies, I will consider a potentially preventive approach to mtDNA-related diseases, namely cytoplasmic transfer. Although successful in primates and 2in preliminary experiments with defective human oocytes, this therapeutic modality requires careful ethical screening.

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