ISSN 0026-8933, Molecular Biology, 2010, Vol. 44, No. 5, pp. 665–681. © Pleiades Publishing, Inc., 2010. Original Russian Text © I.O. Mazunin, N.V. Volodko, E.B. Starikovskaya, R.I. Sukernik, 2010, published in Molekulyarnaya Biologiya, 2010, Vol. 44, No. 5, pp. 755–772. 665 INTRODUCTION Mitochondria play many roles in the cells, but their most important function is to generate energy via oxi- dative phosphorylation (OP). In contrast to other organelles, mitochondria have their own DNA (mtDNA), which codes for several subunits of the complexes involved in OP. Mutations arising in mtDNA may distort energy production and, eventu- ally, cause cell death. Such defects of highly differenti- ated cells of various human tissues and organs lead to various medical conditions [1–3]. It was known for a long time that defects in energy (ATP) production cause certain neuromuscular syndromes [4, 5], but the cause- and- effect relations between known disor- ders/syndromes and mutations of the mtDNA coding region was established far more recently [6–9]. Mito- chondrial disease affects approximately 1 in 10000 adults in the global population. The review considers the modern views of the structure and organization of the mitochondrial genome and the molecular mechanisms of mitochon- drial disorders due to mtDNA mutations. In addition, we compare the molecular methods used to detect mtDNA mutations and experimental strategies aimed at correcting OXPHOS defects. Finally, the means to prevent inheritance of mtDNA mutations are dis- cussed, since this is a pressing problem of mitochon- drial medicine and, in particular, medical genetic counseling. THE STRUCTURE OF THE MITOCHONDRIAL GENOME Human mtDNA is a 16 568-bp circular double- stranded molecule and harbors 37 genes, which are involved in energy production taking place in mito- chondrial respiratory chain. The gene set includes 13 structural genes, which code for subunits of the OXPHOS complexes, and genes for 22 tRNAs and 2 rRNAs, which are involved in protein synthesis directly in mitochondria. The majority of regulatory regions occur in a noncoding region, which is known as the control region (CR) and is 1122 bp in size. During mtDNA replication, the CR forms a 710-bp triple- stranded region the so-called displacement loop (D-loop). The coding sequence accounts for a major part of the mitochondrial genome, and only 87 bp correspond to intercistron regions within this sequence. The CR har- bors heavy-strand (HSP1 and HSP2) and light-strand (LSP) promoters and a heavy-strand replication origin (O H ). A light-strand replication (O L ) origin is outside the CR. The mtDNA strands are characterized by an asymmetric distribution of G/C pairs. The G-rich heavy strand contains both of the rRNA genes, 12 structural genes, and 14 tRNA genes. The remaining eight tRNA genes and one structural gene (ND6) occur in the light strand (Fig. 1a) [12]. Although human mtDNA and prokaryotic DNA share certain structural features (for instance, lack of introns and overlapping genes), the structural organi- zation of the mitochondrial genome is far more intri- cate [13]. It was found that five to seven mtDNA mol- Mitochondrial Genome and Human Mitochondrial Diseases I. O. Mazunin, N. V. Volodko, E. B. Starikovskaya, and R. I. Sukernik Institute of Chemical Biology and Fundamental Medicine, Siberian Branch, Russian Academy of Sciences, Novosibirsk, 630090 Russia; e-mail: ilya.mazunin@yandex.ru Received March 25, 2010 Accepted for publication April 8, 2010 Abstract—Today there are described more than 400 point mutations and more than hundred of structural rearrangements of mitochondrial DNA associated with characteristic neuromuscular and other mitochon- drial syndromes, from lethal in the neonatal period of life to the disease with late onset. The defects of oxida- tive phosphorylation are the main reasons of mitochondrial disease development. Phenotypic diversity and phenomenon of heteroplasmy are the hallmark of mitochondrial human diseases. It is necessary to assess the amount of mutant mtDNA accurately, since the level of heteroplasmy largely determines the phenotypic manifestation. In spite of tremendous progress in mitochondrial biology since the cause-and-effect relations between mtDNA mutation and the human diseases was established over 20 years ago, there is still no cure for mitochondrial diseases. DOI: 10.1134/S0026893310050018 Key words: mitochondrial genome, oxidative phosphorylation, mtDNA mutations, heteroplasmy, mitochon- drial diseases, mitochondrial respiratory chain defect therapy REVIEWS UDC 576.311.347