Chapter 1 The Clinical Spectrum of Nuclear DNA-Related Mitochondrial Disorders Salvatore DiMauro and Valentina Emmanuele Introduction Mitochondrial diseases are conventionally defined as clinical disorders due to defects in the mitochondrial respiratory chain (RC), the terminal pathway of oxidative phos- phorylation (OXPHOS) , where most cellular ATP is generated. This is also the only metabolic pathway that depends on two genomes: mitochondrial DNA (mtDNA) encodes 13 of the ∼ 85 RC proteins and nuclear DNA (nDNA) encodes all remain- ing proteins (Fig. 1.1). The RC is composed of seven discrete functional entities, five multimeric complexes (I–V) and two mobile electron carriers, coenzyme Q 10 (CoQ 10 ) and cytochrome c (cyt c). Among the 13 subunits encoded by mtDNA, seven are components of complex I, one (cytochrome b, cyt b) is part of complex III, three are subunits of complex IV (cytochrome c oxidase, COX), and two are subunits of complexV (ATP synthetase). Complex II (succinate dehydrogenase, SDH) is entirely encoded by nDNA. Due to its dual genetic control, RC defects can be due to mutations in mtDNA or in nDNA. The first mitochondrial diseases to be understood at the molecular level were both due to mtDNA mutations [1, 2], probably because the small mtDNA (16,569 bp) is easily sequenced and because the overt maternal inheritance in one family with Leber hereditary optic neuropathy (LHON) offered a strong clue to the faulty DNA. These seminal papers opened a floodgate of research that associated multiple clinical syndromes as well as nonsyndromic symptoms and signs to mtDNA large- scale rearrangements or point mutations. In short order, mtDNA became a veritable Pandora’s box of human disorders, mostly encephalomyopathies, leading one of the authors to title a review published in 2000: “Mutations in mtDNA: Are we scraping S. DiMauro () College of Physicians & Surgeons, 630 West 168th Street, NewYork, NY 10032, USA e-mail: sd12@columbia.edu Neurology Department, H. Houston Merritt Clinical Research Center, Columbia University Medical Center, NewYork, NY, USA V. Emmanuele Department of Neurology, Columbia University Medical Center, NewYork, NY, USA L.-J. C. Wong (ed.), Mitochondrial Disorders Caused by Nuclear Genes, 3 DOI 10.1007/978-1-4614-3722-2_1, © Springer Science+Business Media, LLC 2013