Abstract
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.
Highlights
Two great discoveries were made in 1988 by two famous researchers, Anita Harding at the Department of Clinical Neurology, Institute of Neurology, Queens Square, London, UK [1], and Doug Wallace at Emory University, Atlanta, GA [2]
The first discovery identified large-scale single deletions of mitochondrial DNA in muscle biopsies from patients with “mitochondrial myopathies” while the second discovery identified a point mutation in the mtDNA gene for subunit 4 of NADH dehydrogenase complex (MTND4), associated with maternally inherited Leber’s hereditary optic neuropathy (LHON) in a large American pedigree. These two discoveries launched a new hunger for human disorders associated with mutations in the tiny mtDNA molecule: In the same year, 1988, our large group of “mitochondriacs” at Columbia University, led by Bud Rowland, clarified the genetic etiology of Kearns–Sayre’s syndrome (KSS), the eponym of Anita Harding’s discovery [3]
The brown stain of c oxidase (COX) prevails over the blue stain of succinate dehydrogenase (SDH) in normal fibers while COX-negative fibers show a bright blue color (“ragged-blue fibers”) and COX-deficient fibers will stain a milder bluish color [10] (Figure 2)
Summary
The first discovery identified large-scale single deletions of mitochondrial DNA (mtDNA) in muscle biopsies from patients with “mitochondrial myopathies” while the second discovery identified a point mutation in the mtDNA gene for subunit 4 of NADH dehydrogenase complex (MTND4), associated with maternally inherited Leber’s hereditary optic neuropathy (LHON) in a large American pedigree. These two discoveries launched a new hunger for human disorders associated with mutations in the tiny mtDNA molecule: In the same year, 1988, our large group of “mitochondriacs” at Columbia University, led by Bud Rowland, clarified the genetic etiology of Kearns–Sayre’s syndrome (KSS), the eponym of Anita Harding’s discovery [3]. Heteroplasmic for mtDNA, divide, they pass on to generation various mutation loads of mtDNA (wild-type and mutant) and, both the genotype and the phenotype may vary in time
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