Pathogenic expression of homoplasmic mtDNA mutations needs a complex nuclear – mitochondrial interaction Valerio Carelli 1,2 , Carla Giordano 3,4 and Giulia d’Amati 3 1 Dipartimento di Scienze Neurologiche, Universita’ di Bologna, Via Ugo Foscolo 7, 40123 Bologna, Italy 2 Doheny Eye Institute and Department of Ophthalmology, University of Southern California/Keck School of Medicine, 1355 San Pablo Street, DVRC 311, Los Angeles, CA 90033-1026, USA 3 Dipartimento di Medicina Sperimentale e Patologia, Universita ` di Roma “La Sapienza”, Viale Regina Elena 324, 00161 Roma, Italy 4 Department of Neurology, College of Physicians and Surgeons, Columbia University, Room 5-431, 630 West 168th Street, New York City, NY 10032, USA Here we define a category of human, maternally inher- ited disorders that are characterized by a homoplasmic mtDNA pathogenic mutation with variable penetrance and a stereotypical clinical expression, usually restricted to a single tissue. Examples of such disorders include Leber’s hereditary optic neuropathy, mitochondrial non-syndromic sensorineural hearing loss, and a form of mitochondrial hypertrophic cardiomyopathy. The mtDNA mutation is necessary, but not sufficient to induce the pathology, and multiple lines of evidence suggest a two-locus genetic model involving a primary mitochondrial mutation and a nuclear modifier. The nuclear modifier does not induce any pathology per se, but it contributes to the pathogenic effect of the mito- chondrial mutation. The nuclear modifier could be a common functional polymorphism in a tissue-specific protein, possibly with mitochondrial location. Human mitochondria contain multiple copies of their own 16569-bp circular DNA, encoding 13 essential components of the OXPHOS (see Glossary) enzymatic complexes, plus genes encoding 22 tRNAs and two rRNAs for their own protein synthesis [1]. Pathogenic mutations in mitochon- drial DNA (mtDNA) are well known to induce a large variety of human diseases (http://www.mitomap.org), most of which are broadly defined as ‘mitochondrial encephalomyopathies’ [2]. According to the peculiar rules of mitochondrial genetics, these multi-systemic disorders can be sporadic or maternally inherited, present a variable clinical expression, and mainly affect highly energy-dependent, post-mitotic tissues, such as the central nervous system, and skeletal and cardiac muscle [2,3]. The pathological consequences of most mtDNA pathogenic mutations on respiratory function are generally severe when the MUTATION LOAD exceeds a certain threshold. Thus, most of these mutations are essentially incompatible with life when HOMOPLASMIC, and they are usually HETEROPLASMIC. The large variability of clinical expression within families bearing the same mutation can be partly accounted for by the variable mutation load in different tissues, obeying their specific energetic threshold. The exceptions to the rules As always, there are exceptions to these rules. Leber’s hereditary optic neuropathy (LHON) is a maternally inherited disorder characterized by selective death of retinal ganglion cells followed by optic nerve atrophy [4]. Most cases of the disease are associated with one of three mtDNA point mutations (G11778A, G3460A, and T14484C) affecting genes encoding complex I (NADH:ubiquinone oxidoreductase) subunits, and currently regarded as pathogenic. A few additional, but infrequent mutations, Glossary Cybrid cells (cybrids): Cancer-derived immortalized cells that are depleted of their own mtDNA by long-term exposure to ethidium bromide (r 0 cells), and have been repopulated with exogenous mitochondria carrying a specific mtDNA mutation by fusion with patient-derived enucleated cells (cytoplasts). Haplogroup J: An mtDNA haplogroup is a group of mtDNAs that is defined by a unique set of variants acquired from the same ancient common female ancestor. Haplogroup J is specific of European and Near Eastern populations with usual frequencies of 7 – 15%, and is defined by the restriction sites þ10394 DdeI, þ4216 NlaIII, and 213704 BstOI. Heteroplasmic mutation: Where mtDNA molecules within a cell are mixed, some harboring a mutation, others being wild type. Heteroplasmy can be intra-mitochondrial and/or inter-mitochondrial. Homoplasmic mutation: All molecules of mtDNA within a cell harbor the same mutation. Mutation load: Percentage of mutant mtDNA copies in the case of hetero- plasmy. Phenocopy: A disorder that mimicks the clinical expression of another, but not sharing the same genetic origin. As a consequence different genetic defects or environmental factors can result in the same clinical phenotype. OXPHOS: Oxidative phosphorylation is the mitochondrial metabolic pathway leading to the proton-motive force ultimately used by ATP-synthase to produce ATP. In fact, this is driven by the energy released through the redox reactions transferring electrons along mitochondrial respiratory chain, and conserved by the coupling with proton translocation across mitochondrial inner membrane, which generates the electrochemical proton gradient. Variable penetrance: In the specific case of homoplasmic mtDNA mutations, this is a variability in the number of individuals expressing the disease compared with the total number of individuals carrying the genetic defect. However, more extensively the clinical expression of the disorder can vary in severity and age of onset. Corresponding author: Valerio Carelli (carelli@neuro.unibo.it). Opinion TRENDS in Genetics Vol.19 No.5 May 2003 257 http://tigs.trends.com 0168-9525/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved. doi:10.1016/S0168-9525(03)00072-6