The history of "mitochondrial pathologies", namely genetic pathologies affecting mitochondrial metabolism because of mutations in nuclear
DNA-encoded genes for
proteins active inside mitochondria or mutations in
mitochondrial DNA-encoded genes, began in 1988. In that year, two different groups of researchers discovered, respectively, large-scale single deletions of
mitochondrial DNA (
mtDNA) in muscle biopsies from patients with "
mitochondrial myopathies" and a point mutation in the
mtDNA gene for subunit 4 of
NADH dehydrogenase (MTND4), associated with maternally inherited
Leber's hereditary optic neuropathy (LHON). Henceforth, a novel conceptual "mitochondrial genetics", separate from mendelian genetics, arose, based on three features of
mtDNA: (1) polyplasmy; (2) maternal inheritance; and (3) mitotic segregation. Diagnosis of
mtDNA-related diseases became possible through genetic analysis and experimental approaches involving histochemical staining of muscle or brain sections, single-fiber polymerase chain reaction (PCR) of
mtDNA, and the creation of patient-derived "cybrid" (cytoplasmic hybrid) immortal fibroblast cell lines. The availability of the above-mentioned techniques along with the novel sensitivity of clinicians to such disorders led to the characterization of a constantly growing number of pathologies. Here is traced a brief historical perspective on the discovery of autonomous pathogenic
mtDNA mutations and on the related mendelian pathology altering
mtDNA integrity.