Mitochondrion and its related disorders: Making a comeback

Mitochondrion and its related disorders: Making a comeback 1 2 3 first-author †E-mail:zhangxianning@zju.edu.cnqiming_14618@yahoo.com †E-mail:zhangxianning@zju.edu.cnqiming_14618@yahoo.com zhangxianning@zju.edu.cn 1 2 †E-mail:zhangxianning@zju.edu.cnqiming_14618@yahoo.com †E-mail:zhangxianning@zju.edu.cnqiming_14618@yahoo.com zhangxianning@zju.edu.cn Zhejiang University-Adinovo Center for Genetic and Genomic Medicine, Zhejiang University, Hangzhou 310058, China Zhejiang University-Adinovo Center for Genetic and Genomic Medicine, Zhejiang University, Hangzhou 310058, China James D. Watson Institute of Genome Sciences, Zhejiang University, Hangzhou 310058, China James D. Watson Institute of Genome Sciences, Zhejiang University, Hangzhou 310058, China National Education Base for Basic Medical Sciences, Zhejiang University, Hangzhou 310058, China National Education Base for Basic Medical Sciences, Zhejiang University, Hangzhou 310058, China The great majority of genetic disorders are caused by defects in the nuclear genome. However, some significant diseases are the result of mitochondrial mutations. Because of the unique features of the mitochondria, these diseases display characteristic modes of inheritance and a large degree of phenotypic variability. Recent studies have suggested that mitochondrial dysfunction plays a central role in a wide range of age-related disorders and various forms of cancer. Mitochondria Mitochondrial disorder Mutation Life is the interplay between structure, energy, and information, yet the role of energy deficiency in human disease has been poorly explored by modern medicine (Wallace, 2005 2005 ). The mitochondria are involved in energy production through the oxidative phosphorylation (OXPHOS) metabolic pathways, and are thus critically important for cell survival (Chan, 2006 2006 ; Wallace, 2007 2007 ). An average eukaryotic cell contains 10 3 ~10 4 copies of mitochondria. A mitochondrion is a semiautonomous, self-reproducing organelle in the cytoplasm of eukaryotic cells and has multiple copies of circular double-stranded mitochondrial DNA (mtDNA) of 16569 base pairs (bp) in man—actually 16568 bp, and 3107del is maintained in the sequence as a gap, “X” (Andrews et al., 1999 1999 ; Http:// www.mitomap.org/mitomap_rCRS.gb.txt www.mitomap.org/mitomap_rCRS.gb.txt ). The human mitochondrial genome consists of approximately 1 500 genes, 37 encoded by the maternally inherited mtDNA and the remainder encoded in the nuclear DNA (nDNA) (Ryan and Hoogenraad, 2007 2007 ). The mtDNA genome is very compact, containing little repetitive DNA. The 37 encoded genes include 2 ribosomal RNA (rRNA), 22 transfer RNA (tRNA) and 13 peptides involved in OXPHOS. The nuclear genome encodes up to 200 factors required for the maintenance and expression of mtDNA or for the assembly of OXPHOS protein complexes. Mutations in many of these nuclear genes can also lead to disorders with the phenotypic characteristics of mtDNA diseases (Liang and Wong, 1998 1998 ; Luoma et al., 2004 2004 ; Zeviani and Carelli, 2007 2007 ). The transcription of mtDNA takes place in the mitochondrion, independent of the nucleus. The mitochondrial genome mutates at a rate about 10-fold greater than nDNA does (Hudson et al., 2005 2005 ). The diseases that result from mutations in mtDNA show distinctive patterns of inheritance due to three features of mitochondrial chromosomes: replicative segregation, homoplasmy and heteroplasmy, and maternal inheritance. When a mutation arises in a cellular mtDNA, it creates a mixed intracellular population of mutant and normal molecules known as heteroplasmy. As a cell divides, it is a matter of chance whether the mutant mtDNA are partitioned into one daughter cell or another. Thus, over time the percentage of mutant mtDNA in different cell lineages can drift toward either pure mutant or normal (homoplasmy), a process called as replicative segregation. The phenotype associated with an mtDNA mutation will depend on the relative proportion of normal and mutant mtDNA in the cells of a particular tissue. As a result, mitochondrial disorders are generally characterized by reduced penetrance, variable expression, and pleiotropy. Hereditary mitochondrial diseases are transmitted only through the maternal line, since spermatozoa contain hardly any mitochondria. Paternal inheritance of mtDNA disorder has been well documented in only one instance (Schwartz and Vissing, 2002 2002 ). Each tissue type requires a certain amount of mitochondrially produced ATP for normal function. Organ system with large ATP requirements and high thresholds, for example, the brain, heart, skeletal muscle, eye, ear, liver, pancreas and kidney, tend to be the ones most seriously affected by mitochondrial diseases. The first inherited pathogenic mtDNA mutations were discovered in 1988, when Wallace et al. ( 1988 1988 ) reported the mtDNA mutation that causes Leber hereditary optic neuropathy (LHON, OMIM 535000), a form of middle life blindness, and subsequently the mutation that causes myoclonic epilepsy and ragged red fiber disease (MERRF, OMIM 545000), a progressive epilepsy with muscle weakness. Since then, a large number of mtDNA mutations have been linked to familial symptoms, including forms of blindness, deafness, dementia, stroke-like episodes, migraines, movement disorders, cardiomyopathy, renal dysfunction, diabetes, various forms of cancer, etc. (Wallace, 2005 2005 ; Zeviani and Carelli, 2007 2007 ). Three types of mutations have been identified in mtDNA: (1) Missense mutations in protein-coding mtDNA genes that alter the activity of an OXPHOS protein. mtDNA missense mutations can be associated with two common ophthalmologic manifestations, optic atrophy and retinitis pigmentosa; (2) Single-base mutations in tRNA or rRNA genes that impair mitochondrial protein synthesis. The example diseases are MERRF and MELAS (mitochondrial encephalomyopathy, lactic acidosis and strokelike episodes, OMIM 540000); (3) Rearrangements that consist of duplications and deletions of the mtDNA molecule. These can produce Kearns-Sayre disease (muscle weakness, cerebellar damage, and heart failure, OMIM 530000), Pearson syndrome (infantile pancreatic insufficiency, pancytopenia, and lactic acidosis, OMIM 557000), and chronic progressive external ophthalmoplegia (CPEO). The disease-causing mutations seen in mtDNA include more than 50 point mutations and more than 100 deletions or duplications. Since the mitochondria use OXPHOS to convert dietary calories into usable energy, generating reactive oxygen species (ROS) as a toxic by-product, mitochondrial dysfunction plays a central role in a wide range of age-related disorders and various forms of cancer (Wallace, 2007 2007 ; Xia et al., 2007 2007 ; Zeviani and Carelli, 2007 2007 ). Increased amount of rearrangements (deletions/small duplications) and point mutations of mtDNA have been reported during aging in several mammalian species. Studies of different tissues have shown that the somatic mtDNA mutations are not always evenly distributed but can accumulate clonally in single cells and cause a severe respiratory chain deficiency in these cells. It is probable that clonal expansion of pathogenic mtDNA mutations in individual cells will lead to their loss with age, but it is unclear how this phenomenon will affect organismal survival (Trifunovic et al., 2004 2004 ). The tissue-specific manifestations of these diseases may result from the varying energetic roles and needs of the different tissues. The variation in the individual and regional predisposition to degenerative diseases and cancer may result from the interaction of modern dietary caloric intake and ancient mitochondrial genetic polymorphisms (Pospisilik et al., 2007 2007 ). Therefore the mitochondria provide a direct link between our environment and our genes, and the mtDNA variants that permit our forbears to energetically adapt to their ancestral homes are influencing our health today (Calvo et al., 2006 2006 ; Wallace, 2007 2007 ). References RM Andrews , I Kubacka , PF Chinnery , RN Lightowlers , DM Turnbull , N Howell . Reanalysis and revision of the Cambridge reference sequence for human mitochondrial DNA . Nat Genet , 1999 . 23 ( 2 ): 147 DOI: 10.1038/13779 http://doi.org/10.1038/13779 . Reanalysis and revision of the Cambridge reference sequence for human mitochondrial DNA S Calvo , M Jain , X Xie , SA Sheth , B Chang , OA Goldberger , A Spinazzola , M Zeviani , SA Carr , VK Mootha . Systematic identification of human mitochondrial disease genes through integrative genomics . Nat Genet , 2006 . 38 ( 5 ): 576 - 582 . DOI: 10.1038/ng1776 http://doi.org/10.1038/ng1776 . Systematic identification of human mitochondrial disease genes through integrative genomics DC Chan . Mitochondria: Dynamic organelles in disease, aging, and development . Cell , 2006 . 125 ( 7 ): 1241 - 1252 . DOI: 10.1016/j.cell.2006.06.010 http://doi.org/10.1016/j.cell.2006.06.010 . Mitochondria: Dynamic organelles in disease, aging, and development G Hudson , S Keers , PY Man , P Griffiths , K Huoponen , ML Savontaus , E Nikoskelainen , M Zeviani , F Carrara , R Horvath , 等 . Identification of an X-chromosomal locus and haplotype modulating the phenotype of a mitochondrial DNA disorder . Am J Hum Genet , 2005 . 77 ( 6 ): 1086 - 1091 . DOI: 10.1086/498176 http://doi.org/10.1086/498176 . Identification of an X-chromosomal locus and haplotype modulating the phenotype of a mitochondrial DNA disorder MH Liang , LJ Wong . Yield of mtDNA mutation analysis in 2000 patients . Am J Med Genet , 1998 . 77 ( 5 ): 395 - 400 . DOI: 10.1002/(SICI)1096-8628(19980605)77:5<395::AID-AJMG8>3.0.CO;2-M http://doi.org/10.1002/(SICI)1096-8628(19980605)77:5<395::AID-AJMG8>3.0.CO;2-M . Yield of mtDNA mutation analysis in 2000 patients P Luoma , A Melberg , JO Rinne , JA Kaukonen , NN Nuponen , RM Chalmers , A Oldfors , I Rautakorpi , L Peltonen , K Majamaa , 等 . Parkinsonism, premature menopause, and mitochondrial DNA polymerase gamma mutations: Clinical and molecular genetic study . Lancet , 2004 . 364 ( 9437 ): 875 - 882 . DOI: 10.1016/S0140-6736(04)16983-3 http://doi.org/10.1016/S0140-6736(04)16983-3 . Parkinsonism, premature menopause, and mitochondrial DNA polymerase gamma mutations: Clinical and molecular genetic study JA Pospisilik , C Knauf , N Joza , P Benit , M Orthofer , PD Cani , I Ebersberger , T Nakashima , R Sarao , G Neely , 等 . Targeted deletion of AIF decreases mitochondrial oxidative phosphorylation and protects from obesity and diabetes . Cell , 2007 . 131 ( 3 ): 476 - 491 . DOI: 10.1016/j.cell.2007.08.047 http://doi.org/10.1016/j.cell.2007.08.047 . Targeted deletion of AIF decreases mitochondrial oxidative phosphorylation and protects from obesity and diabetes MT Ryan , NJ Hoogenraad . Mitochondrial-nuclear communications . Annu Rev Biochem , 2007 . 76 ( 1 ): 701 - 722 . DOI: 10.1146/annurev.biochem.76.052305.091720 http://doi.org/10.1146/annurev.biochem.76.052305.091720 . Mitochondrial-nuclear communications M Schwartz , J Vissing . Paternal inheritance of mitochondrial DNA . N Engl J Med , 2002 . 347 ( 8 ): 576 - 580 . DOI: 10.1056/NEJMoa020350 http://doi.org/10.1056/NEJMoa020350 . Paternal inheritance of mitochondrial DNA A Trifunovic , A Wredenberg , M Falkenberg , JN Spelbrink , AT Rovio , CE Bruder , YM Bohlooly , S Gidlof , A Oldfors , R Wibom , 等 . Premature ageing in mice expressing defective mitochondrial DNA polymerase . Nature , 2004 . 429 ( 6990 ): 417 - 423 . DOI: 10.1038/nature02517 http://doi.org/10.1038/nature02517 . Premature ageing in mice expressing defective mitochondrial DNA polymerase DC Wallace . A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: A dawn for evolutionary medicine . Annu Rev Genet , 2005 . 39 ( 1 ): 359 - 407 . DOI: 10.1146/annurev.genet.39.110304.095751 http://doi.org/10.1146/annurev.genet.39.110304.095751 . A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: A dawn for evolutionary medicine DC Wallace . Why do we still have a maternally inherited mitochondrial DNA? Insights from evolutionary medicine . Annu Rev Biochem , 2007 . 76 ( 1 ): 781 - 821 . DOI: 10.1146/annurev.biochem.76.081205.150955 http://doi.org/10.1146/annurev.biochem.76.081205.150955 . Why do we still have a maternally inherited mitochondrial DNA? Insights from evolutionary medicine DC Wallace , G Singh , MT Lott , JA Hodge , TG Schurr , AM Lezza , LJ2nd Elsas , EK Nikoskelainen . Mitochondrial DNA mutation associated with Leber’s hereditary optic neuropathy . Science , 1988 . 242 ( 4884 ): 1427 - 1430 . DOI: 10.1126/science.3201231 http://doi.org/10.1126/science.3201231 . Mitochondrial DNA mutation associated with Leber’s hereditary optic neuropathy C Xia , Q Meng , LZ Liu , Y Rojanasakul , XR Wang , BH Jiang . Reactive oxygen species regulate angiogenesis and tumor growth through vascular endothelial growth factor . Cancer Res , 2007 . 67 ( 22 ): 10823 - 10830 . DOI: 10.1158/0008-5472.CAN-07-0783 http://doi.org/10.1158/0008-5472.CAN-07-0783 . Reactive oxygen species regulate angiogenesis and tumor growth through vascular endothelial growth factor M Zeviani , V Carelli . Mitochondrial disorders . Curr Opin Neurol , 2007 . 20 ( 5 ): 564 - 571 . . Mitochondrial disorders 10.1631/jzus.B0710621 Project supported by the Natural Science Foundation of Zhejiang Province (No. 2007C33049), China 2007-12-04 2007-12-27 2008-01-06 2022-01-05 Copyright © 2008, Journal of Zhejiang University Science 2008 Journal of Zhejiang University-SCIENCE B (Biomedicine and Biotechnology) 02 09