title: Unsolved issues related to human mitochondrial diseases.
abstract: Human mitochondrial diseases, defined as the diseases due to a mitochondrial oxidative phosphorylation defect, represent a large group of very diverse diseases with respect to phenotype and genetic causes. They present with many unsolved issues, the comprehensive analysis of which is beyond the scope of this review. We here essentially focus on the mechanisms underlying the diversity of targeted tissues, which is an important component of the large panel of these diseases phenotypic expression. The reproducibility of genotype/phenotype expression, the presence of modifying factors, and the potential causes for the restricted pattern of tissular expression are reviewed. Special emphasis is made on heteroplasmy, a specific feature of mitochondrial diseases, defined as the coexistence within the cell of mutant and wild type mitochondrial DNA molecules. Its existence permits unequal segregation during mitoses of the mitochondrial DNA populations and consequently heterogeneous tissue distribution of the mutation load. The observed tissue distributions of recurrent human mitochondrial DNA deleterious mutations are diverse but reproducible for a given mutation demonstrating that the segregation is not a random process. Its extent and mechanisms remain essentially unknown despite recent advances obtained in animal models.
authors: Inserm Institut Cochin U1016, CNRS UMR 8104, 24 rue du Fb St Jacques, Paris F-75014, France; Université Paris-Descartes-Paris5, Paris F-75014, France; AP-HP, Service de Biochimie Métabolique et Centre de Génétique moléculaire et chromosomique, GHU Pitié-Salpêtrière, Paris F-75651, France. Electronic address: anne.lombes@inserm.fr.
authors: Anne
authors: A
authors: Lombès
authors: Inserm Institut Cochin U1016, CNRS UMR 8104, 24 rue du Fb St Jacques, Paris F-75014, France; AP-HP, Hôpital Ambroise Paré, Service d'explorations fonctionnelles, Boulogne-Billancourt F-92100, France; Université Versailles-Saint-Quentin en Yvelines, Faculté de Médecine, F-78180, France. Electronic address: karine.aure@apr.aphp.fr.
authors: Karine
authors: K
authors: Auré
authors: AP-HP, Service de Biochimie Métabolique et Centre de Génétique moléculaire et chromosomique, GHU Pitié-Salpêtrière, Paris F-75651, France. Electronic address: Christine.bellanne-chantelot@psl.aphp.fr.
authors: Christine
authors: C
authors: Bellanné-Chantelot
authors: Inserm Institut Cochin U1016, CNRS UMR 8104, 24 rue du Fb St Jacques, Paris F-75014, France; AP-HP, Service de Biochimie Métabolique et Centre de Génétique moléculaire et chromosomique, GHU Pitié-Salpêtrière, Paris F-75651, France. Electronic address: mylene.gilleron@psl.aphp.fr.
authors: Mylène
authors: M
authors: Gilleron
authors: Inserm Institut Cochin U1016, CNRS UMR 8104, 24 rue du Fb St Jacques, Paris F-75014, France; AP-HP, Service de Biochimie Métabolique et Centre de Génétique moléculaire et chromosomique, GHU Pitié-Salpêtrière, Paris F-75651, France. Electronic address: claude.jardel@psl.aphp.fr.
authors: Claude
authors: C
authors: Jardel
mesh_terms: D000818:Animals; D046528:Chimerism; D004272:DNA, Mitochondrial / Q000235:genetics* / Q000378:metabolism*; D005786:Gene Expression Regulation; D018740:Genetic Heterogeneity; D005838:Genotype; D006801:Humans; D040582:Inheritance Patterns; D008928:Mitochondria / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D028361:Mitochondrial Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D024101:Mitochondrial Proteins / Q000235:genetics* / Q000378:metabolism; D008938:Mitosis; D009154:Mutation; D009928:Organ Specificity; D010641:Phenotype
chemical_list: D004272:DNA, Mitochondrial; D024101:Mitochondrial Proteins
keywords: Heteroplasmy; Human diseases; Mitochondrial DNA; Oxidative phosphorylation; Tissue specificity