Published May 23, 2011

JCB: Review

Mitochondrial DNA mutations in disease and aging
Chan Bae Park1 and Nils-Göran Larsson2
1 2

Institute for Medical Sciences, Ajou University School of Medicine, Suwon 443-721, Korea Max Planck Institute for Biology of Ageing, D-50931 Cologne, Germany


The small mammalian mitochondrial DNA (mtDNA) is very gene dense and encodes factors critical for oxidative phosphorylation. Mutations of mtDNA cause a variety of human mitochondrial diseases and are also heavily implicated in age-associated disease and aging. There has been considerable progress in our understanding of the role for mtDNA mutations in human pathology during the last two decades, but important mechanisms in mitochondrial genetics remain to be explained at the molecular level. In addition, mounting evidence suggests that most mtDNA mutations may be generated by replication errors and not by accumulated damage.

the hydrophobicity of the gene products, which may prevent mitochondrial import if the gene is relocated to the nucleus. Approximately 25% of the yeast mitochondrial proteome of 750–1,000 proteins is dedicated to maintenance and expression of mtDNA (Sickmann et al., 2003). This means 200–250 nucleus-encoded proteins are needed to express a handful of mtDNA-encoded proteins, and it is unclear why this costly arrangement has been maintained throughout evolution if the only reason is the hydrophobicity of certain gene products. An interesting alternate hypothesis proposes that mtDNA has been kept for a regulatory purpose and that the biogenesis of the oxidative phosphorylation system requires direct interactions between the respiratory chain subunits and mtDNA (Allen, 2003).
Transcription and replication of mammalian mtDNA

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The origin of mtDNA

The mitochondrial oxidative phosphorylation system is remarkable in its dependence on both nuclear- and mitochondrial DNA (mtDNA)-encoded subunits (Falkenberg et al., 2007). The involvement of two distinct genomes creates a demand for elaborate regulatory processes to coordinate gene expression in response to cellular demands for ATP synthesis (Falkenberg et al., 2007). Mitochondria are related to -protobacteria, and the eukaryotic cell arose approximately two billion years ago by some type of fusion event between ancient cells related to -protobacteria and archaebacteria (Yang et al., 1985; Lang et al., 1997; Andersson et al., 1998). Phylogenetic comparisons have shown that there is always cosegregation between the presence of mtDNA and a functional respiratory chain (Burger et al., 2003; Wallace, 2007). There is ongoing traffic of mtDNA fragments to the nucleus (Thorsness and Fox, 1990), and genes for many respiratory chain subunits have been transferred to the nucleus during evolution (Burger et al., 2003; Wallace, 2007). However, the genes for cytochrome b and cytochrome c oxidase subunit I are always maintained in mtDNA of the many organisms that have been studied to date (Wallace, 2007). The reason for the localization of these genes to mtDNA could be
Correspondence to Nils-Göran Larsson: Abbreviations used in this paper: ES, embryonic stem; HSP, heavy strand promoter; LSP, light strand promoter; mtDNA, mitochondrial DNA; MTERF, mitochondrial transcription termination factor; ROS, reactive oxygen species; rRNA, ribosomal RNA.

Mammalian mtDNA encodes 13 proteins that all are subunits of the oxidative phosphorylation system and 22 tRNAs and 2 ribosomal RNAs (rRNAs; Fig. 1). The transcription of mtDNA is polycistronic and is initiated at one main promoter on each strand, the light strand promoter (LSP) and heavy strand promoter (HSP). The existence of a second HSP dedicated to the transcription of the rRNA genes has been reported (Montoya et al., 1983; Martin et al., 2005); however, its existence has been questioned, as transcription from this putative promoter cannot be reconstituted in vitro with known components of the basal transcription machinery (Litonin et al., 2010). The steady-state levels of rRNAs are much higher than the levels of the downstream mRNAs, but this is, in principle, compatible with polycistronic transcription from a single HSP as the rRNAs are incorporated into ribosomes and therefore may be much more stable than the downstream mRNAs. The basal machinery needed for transcription initiation of mtDNA has been fully reconstituted in vitro and consists of a set of three proteins: mitochondrial RNA polymerase (POLRMT), mitochondrial transcription factor B2 (TFB2M), and mitochondrial transcription factor A (TFAM; Falkenberg et al., 2002). Interestingly, POLRMT is most closely related to bacteriophage RNA polymerases (Shutt and Gray, 2006a) and in addition contains a large N-terminal extension that may have a role in coupling transcription to translation (Rodeheffer and Shadel, 2003).
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The Rockefeller University Press J. Cell Biol. Vol. 193 No. 5  809–818



Kaufman et al. (c) the protein should be suffi­ ciently abundant to coat mtDNA. 2002. Bogenhagen et al. ND4L.. 2011 Figure 1. W. which is at the resolution limit of confocal microscopy. H. The origin of lagging strand replication (OL) is embedded in a cluster of tRNA genes. TFAM is not only a transcription factor but also functions as an mtDNA packaging protein (Larsson et al. G. L1. COI–III. 2009).. and future studies are clearly warranted.. and ATP8). 2004) have suggested that each nucleoid contains two to eight mtDNA molecules. V. S2. Y. and 22 tRNAs (F. S1. ATP6. Understanding this issue will provide novel insights into principles for mitotic segregation and maternal transmission of mtDNA. Pellegrini et al. thus arguing that TFAM fully coats mtDNA in vivo.g. (d) the protein should colocalize with mtDNA on high-resolution microscopy. It is important to apply novel high-resolution optic microscopy techniques to determine whether 250 nm is the true size of the nucleoids and how uniform the size is. E.. I.Published May 23. Ekstrand et al. Litonin et al. 2008). and  810 JCB • VOLUME 193 • NUMBER 5 • 2011 immunofluorescence experiments show a perfect colocalization between TFAM and mtDNA (Garrido et on August 17. 13 mRNAs (ND1–6.. In budding yeast. the displacement loop (D loop) region. Biochemical studies further support the conclusion that TFB2M is essential for transcription. The estimated size of the nucleoid in mammalian cells is 250 nm. and genetic experiments.. Another fundamental question is whether all nucleoids have an equal protein composition and how a particular nucleoid is selected for transcription and/or replication of mtDNA. McCulloch and Shadel. It is currently unknown whether the nucleoids in mammalian cells are free in the mitochondrial matrix or whether they are attached to the inner mitochondrial membrane. Kaufman et al. TFB1M conditional knockout mice have severely impaired translation and are able to activate mitochondrial transcription.rupress. 2009). 1992.. R. There is approximately one TFAM molecule/10–20 bp mtDNA in mouse tissues (Ekstrand et al. showing that there seems to be no functional redundancy between TFB1M and TFB2M (Metodiev et al. A. Cyt b. 2012 . (b) the protein should have intrinsic biophysical properties consistent with packaging DNA. The doublestranded circular mammalian mtDNA molecule of 16. TFB1M was initially reported to have a role in mitochondrial transcription (Falkenberg et al. e. Future studies of the nucleoid are therefore likely to give very fundamental insights into mammalian mitochondrial biology. but a conditional mouse knockout model has shown that it instead is an essential rRNA methyltransferase necessary for the integrity of the small subunit of the mitochondrial ribosome (Metodiev et al.5 kb contains a single longer noncoding region. This raises the interesting question of whether each nucleoid contains only one mtDNA genotype or whether there may be a mixture of mutant and wild-type mtDNA in a single nucleoid. 1998. Our understanding of the regulation of the basal transcription initiation machinery is rather limited despite the fact that there is a long list of nuclear transcription regulators that are proposed to have intramitochondrial isoforms. 2004.. and Q) are indicated by boxes. Illustration by Annika Röhl. 2010). and (e) the protein should be essential for maintenance of mtDNA in vivo. The genes for the two rRNAs (12S and 16S rRNA).. where they dimethylate two highly conserved adenines at a stem-loop structure at the 3 end of the small subunit rRNA (Shutt and Gray. The paralogues TFB1M and TFB2M in mammalian cells are related to a highly conserved family of dimethyl adenosine methyltransferases (Falkenberg et al.. We propose that the definition of the nucleoid should focus on the role of the protein components in packaging and organizing mtDNA and that structural nucleoid proteins should comply with the following criteria: (a) the protein should interact with mtDNA (copurification or cross-linking). harboring the promoters for transcription of both mtDNA strands (HSP and LSP) and the origin of leading strand replication (OH).. M.. 2007. 2003). showing that the studied protein can be cross-linked to and/or copurified with mtDNA. showing that the gene encoding the studied protein is essential for maintenance of mtDNA (Chen et al. 1991) and can wrap.  Schematic representation of mammalian mtDNA. and compact DNA (Fisher et al. N. L2. Genetic experiments in the mouse show that mtDNA levels in vivo are regulated according to levels of TFAM (Ekstrand et al. It belongs to the high mobility group domain proteins (Parisi and Clayton. 2006b). bend. orphan receptors..... 2009. as a protein may interact with mtDNA and be necessary for maintenance of mtDNA without having a role in packaging and organizing mtDNA. as discussed in the “Principles for maternal inheritance of mtDNA” section. 2004). K. 2004). as it is a component of the catalytic site of POLRMT necessary for transcription initiation (Sologub et al. and other transcription Downloaded from jcb. P. 2009). This concept is not straightforward... Confocal microscopy experiments (Legros et al. 2005). C. and these genomes are packaged into mtDNA protein aggregates called nucleoids (Satoh and Kuroiwa. TFAM is currently the only mammalian protein that has been shown to fulfill all of these criteria. and eukaryotes (mitochondria and the nucleus). There are thousands of mtDNA copies in a mammalian somatic cell. 2007). 2003). T. nuclear hormone receptors. archaebacteria. a large number of proteins have been defined as components of the nucleoid based on a combination of biochemical experiments. 1991.. 2002) that are present in bacteria. D. Definition of the structure of the nucleoid is a very fundamental question in mitochondrial genetics.

1991.. 2010)..Published May 23. 1995. These mice developed clinical symptoms if they had a proportion of >20% respiratory chain– deficient neurons. We have previously presented a more detailed discussion of these models (Falkenberg et al. 2006). 2001.. 2009). Fusté et al. Unfortunately.. OL. the strand-coupled model argues that the replication of the leading and lagging strands is synchronous (Holt et al.. 2001). Lee et al. The mutation load can vary widely between members of the same family and in different cells of particular tissues. 2010).. and a particular mtDNA molecule may be replicated many times or not at all as a cell divides (Bogenhagen and Clayton. Replication of mtDNA is dependent on POLRMT that forms the short RNA primers needed for initiation of mtDNA replication at the heavy and light strand replication origins (OH and OL... However. 1988. Brown et al. 1991). Interestingly. 2008). The atomic structure for the Pol- was recently solved and showed that the complex is heterotrimeric and consists of one Pol- A subunit and two Pol- B subunits (Carrodeguas et al.. The mitochondrial transcription termination factors (MTERFs) are exclusively localized to mitochondria. the twinkle DNA helicase (Spelbrink et al.. 2010) and in transcription initiation (Martin et al. but few relevant animal models are available (Table I). and LSP. 1982. Wenz et al. 2006).. 1988. a condition called heteroplasmy. According to the strand-asymmetric model. Atomic structures of MTERF1 (Yakubovskaya et al.. mouse chimeras with mosaic respiratory chain deficiency in pyramidal neurons of the cerebral cortex were generated (Dufour et al. Yasukawa et al. Wallace et al. and the mitochondrial single-stranded DNA–binding protein (Falkenberg et al. 1997. Recent data show that POLRMT specifically recognizes the stem-loop structure at OL and provides a primer for initiation of lagging strand mtDNA synthesis at this site (Fusté et al..rupress. In an experimental study. Mammalian mitochondrial genetics • Park and Larsson 811 . whereby respiratory chain–deficient neurons induce death of neighboring neurons with normal respiratory chain function. Any valid model for mtDNA replication must therefore explain the role of these regulatory sequence elements in mtDNA replication. 2009. the MTERF motif.. The mitotic segregation of heteroplasmic mtDNA mutations in somatic tissues and the principles for maternal transmission of mtDNA (the bottleneck phenomenon and the purifying selection) are cornerstones in mammalian mitochondrial genetics. but the deleted mtDNA molecule always retains OH. 2010) and MTERF3 (Spåhr et al. 1971).. 2007. the leading strand replication is two thirds complete before lagging strand replication is initiated (Clayton. a transneuronal degeneration phenomenon. There are many reported patients with high levels of mtDNA molecules with a single large deletion. 2007). 2011 factors (Shutt and Shadel... The location of the deletion often varies between patients.. 2005).. Zeviani and Di Donato. which makes segregation of mtDNA mutations possible also in postmitotic cells.. 2000. Falkenberg and Larsson. 2008). 2). there are also reports that seemingly neutral polymorphisms in mtDNA may undergo directional selection in certain tissues (Jenuth et al. which has for >20 yr been implicated in transcription termination to enhance the production of rRNAs (Kruse et al. and the mechanisms are therefore poorly understood. 2001. and the defect caused mortality if there were >60–80% defective neurons (Dufour et al. 1982. Jokinen et on August 17. It is generally assumed that mitotic segregation of pathogenic mtDNA mutations is a largely random process and that high mutation levels may be selected against in rapidly dividing cells. A combination of biochemical and genetic approaches will be necessary to further clarify the mode of mtDNA replication in mammalian mitochondria. Increased molecular understanding of these processes would lead to new understanding of disease pathophysiology and would also improve genetic counseling in families with mitochondrial disease.. Munnich and Rustin. and the first described member of this family is MTERF1.. 2000. which varies depending on the type of mutation and the type of affected tissue. These discoveries were important breakthroughs that led to a genetic basis for the classification of mitochondrial disease and revealed novel insights into mitochondrial genetics. 1977). 2010). Lee et al. 2010). The mode of mtDNA replication is controversial. Clayton. 1989. Brown et al. Segregation of mutated mtDNA in somatic tissues Downloaded from jcb. 2012 Pathogenic mtDNA mutations were first reported in human patients >20 yr ago (Holt et al. The minimal replisome needed for replication of mtDNA consists of the mtDNA polymerase (Pol-. was also observed (Dufour et al. Thus. Battersby and Shoubridge.. Yasukawa et al. Larsson. Heteroplasmic mtDNA mutations will only cause respiratory chain dysfunction if present above a certain threshold (Fig.. This mosaicism is likely an important determinant in disease pathophysiology. these phenomena are poorly understood at the cell biological level despite their fundamental importance.. Replication of mtDNA is not linked to the cell cycle. 1988). 2).. The paralogues MTERF2 and MTERF3 have roles in transcription initiation regulation (Park et al. 2010) have unexpectedly shown that these proteins are very similar and contain repeated modules of a novel nucleic acid–binding fold. 2009). 2008).. thus arguing that these sequences are essential for mtDNA replication (Moraes et al. Pathogenic mutations of mtDNA are often heteroplasmic A large number of pathogenic mtDNA mutations are known. as two competing models have been advocated: the strand-asymmetric (Clayton. 2009a). and half-lives of 14 d have been reported in the rat brain and other tissues (Menzies and Gold. This mode of replication makes it possible for a single mutational event to expand clonally or be lost as the cell divides (Fig. there is likely continuous replication of mtDNA in all tissues. In contrast. 2001. 2010). The turnover of mtDNA in differentiated tissues has not been extensively studied. 2007. 2004). This uneven distribution of mutated mtDNA leads to a mosaic respiratory chain deficiency in affected tissues. Zeviani et al. and only a few comments will be made here.. 2005). and the reader is referred to specialized reviews on the associated clinical phenotypes (Larsson and Clayton. 2005) and the strand-coupled replication modes (Holt et al. Yakubovskaya et al. Patients harboring pathogenic mtDNA mutations often have a mixture of wild-type and mutated molecules.

2008 Impaired respiratory chain function. 2010 Tyynismaa et al... early mortality Embryonic lethality. embryonic lethality Respiratory chain deficiency in skeletal muscle. embryonic stem. Studies of mammalian cell lines have shown that Parkin.. 13885insC. 2008 Akman et al.. 2007 Silva et al. cardiomyophathy References Trifunovic et al.  Mouse models for mtDNA mutation Model mtDNA point mutation Mutator mouse (POLGA D257A) Trans-mitochondrial mice (CAPR) Trans-mitochondrial mouse (T6589C) Trans-mitochondrial mouse (T6589C + 13885insCdelT) mtDNA deletion Trans-mitochondrial mouse (mtDNA4696) Deletor mouse (Twinkle dup353–365) Mito-PstI mouse mtDNA depletion TFAM/ TFAM/ heart TFAM/ forebrain neuron TFAM/ dopaminergic neuron TFAM/ pancreatic  cell POLGA/ MFN1/ + MFN2/ skeletal muscle TK2/ TK2 H126N Experimental manipulation Knockin modification of DNA polymerase  exonuclease domain Cytoplasmic transfer of chloramphenicolresistant mtDNAs to ES cells Cytoplasmic transfer of mtDNA with T6589C missense mutation to ES cells Cytoplasmic transfer of mtDNA with T6589C. early mortality Growth retardation. 2010 Downloaded from jcb.. growth retardation Decreased complex IV activity. The evidence for the existence of this mitochondrial quality control mechanism in mammals is at present based on forced expression of Parkin in transformed cell lines in combination with the use of rather drastic mitochondrial toxins (Narendra et al. renal failure.. 2007. 2012 RRM2B/ RNASEH1/ mtDNA increase PAC-hTFAM TFAM-EGFP CAG-hTFAM Skeletal muscle–specific knockout of MFN1 and MFN2.. Hokari et al. muscle atrophy.. 2000 Tyynismaa et al. Hoppins et al. Autophagocytosis has an important role in vivo to remove mitochondria during normal erythrocyte differentiation  812 JCB • VOLUME 193 • NUMBER 5 • 2011 (Sandoval et al. 1999 Sörensen et al... Respiratory chain deficiency leads to a fragmentation of the mitochondrial network in cell lines and mouse tissues (Duvezin-Caubet et al. 2009. early mortality Growth retardation. Suen et al. as exemplified by the finding that blocked fusion leads to loss of mtDNA (Chen and Chan. 2008 Bourdon et al. 2004 Ylikallio et al. 2010)... an E3-ubiquitin ligase mutated in juvenileonset Parkinson’s disease..Published May 23. encoding p53controlled ribonucleotide reductase (p53R2) Knockout of mitochondrial ribonuclease H1 (RNaseH1) Transgenic expression of P1 artificial chromosome containing human TFAM Transgenic expression of TFAM-EGFP fusion protein Transgenic expression of mouse TFAM cDNA under CAG promoter Transgenic expression of mouse TWINKLE cDNA Transgenic expression of mouse TWINKLE cDNA and human TFAM cDNA Zhou et al.. myopathy.. 2003 Ekstrand et al.. 2004 Nishiyama et al. 2008... 2010). 2006 Fan et al. 2010. 2011 Table I. These processes ensure mixing of the gene product content of the mitochondrial network in a cell and are necessary for maintaining function. 1999. Kimura et al.454) to pronuclear stage embryo Transgenic expression of mutant mtDNA helicase twinkle Skeletal muscle–specific expression of mitocho­ ndrially targeted PstI restriction endonuclease Knockout of TFAM in whole body Knockout Knockout Knockout Knockout Knockout of of of of of TFAM in TFAM in TFAM in TFAM in POLGA cardiomyocyte forebrain dopaminergic neuron pancreatic  cell Phenotype Impaired respiratory chain function. muscle atrophy. and 13885insCdelT mutation to ES cells Cytoplasmic transfer of deleted mtDNA (7. myopathy Respiratory chain deficiency. 2005 Marchington et al. renal failure. 2010 Ikeuchi et al. delay neuronal cell death No apparent pathophysiology Progressive respiratory chain dysfunction Inoue et al. early mortality Impaired respiratory chain function in brain.759–12... Kujoth et al. 1998 Wang et al... respiratory chain deficiency No apparent pathophysiology Improve mitochondrial disease phenotypes Improve cardiac failure after myo­cardial infarction.. embryonic lethality Dilated cardiomyopathy Neurodegenerative symptoms Parkinson’s disease symptoms Mitochondrial diabetes Respiratory chain deficiency. 2006)..rupress. growth retardation. myopathy. Suen et al. 2009.. 2008.. 2010).. translocates to dysfunctional mitochondria to promote degradation by autophagocytosis (Narendra et al. 2000 Kasahara et al. 2007). 2010. Mitochondria form a dynamic network undergoing continuous fusion and fission (Detmer and Chan.. Sligh et al. Human patients with mitochondrial disease . 2005 Chen and Chan. 2000 Hance et al. cardiomyopathy Impaired respiratory chain function.. 2001 Ekstrand et al. GTPases essential for mitochondrial fusion Knockout of thymidine kinase 2 (TK2) Knockin modification of TK2 found in human mtDNA depletion syndrome patients (TK2 H126N) Knockout of RRM2B gene. 2005 Srivastava and Moraes. 2007.. 2005. 2010 TWINKLE Twinkle + hTFAM ES. 2005 Larsson et al. premature aging phenotypes Growth retardation.. early mortality Progressive decrease of respiratory chain function Impaired respiratory chain function in skeletal muscle. on August 17. 2003 Cerritelli et al. 2008)..

2008a). 2008b). 1992).. A similar rapid segregation was soon observed in many human pedigrees transmitting heteroplasmic pathogenic mtDNA mutations (Larsson et al. There is a clear need to verify that the mitochondrial quality control mechanism observed in cell lines is relevant for mammals in vivo. This segregation phenomenon is attributed to a bottleneck mechanism in the female germline. 2009.. There is no synchronization between cell division and mtDNA replication. 2011 Figure 2. apparently random. but the level of mutated mtDNA (red dots) is very low in comparison with normal mtDNA (green dots). Mutations of tRNA or rRNA genes are more likely than amino acid substitutions to escape the purifying selection in the mouse maternal germline. Mammalian mitochondrial genetics • Park and Larsson 813 Downloaded from jcb..Published May 23.. Cree et al. Formally. and accumulation of mutated mtDNA above a certain threshold level will lead to impaired respiratory chain function. Giles et al. e. 2008. 2008a). 3).... the bottleneck mechanism could also prevent the spread of low levels of deleterious mtDNA mutations in maternal lineages (Stewart et al. Several studies have produced conflicting results proposing that the bottleneck for mtDNA transmission occurs at different stages in the maternal germline. 2004) shows a strong selection against amino acid replacement mutations...g. Principles for maternal inheritance of mtDNA Maternal transmission of mammalian mtDNA has been recognized for >35 yr (Hutchison et al. 2008a. Such a mechanism could involve fragmentation of the mitochondrial network during some stage of oocyte development to permit expression of individual mtDNA molecules and subsequent functional readout of respiratory chain function in single mitochondria (Stewart et al. but it could also represent an independent protective mechanism.. However. Available data on the nature of the bottleneck are mainly correlative. as it involves blocking replication or destroying mutant mtDNA genomes without the need for testing the function of the gene products encoded by the mutant genome. 1996). 2008.rupress. and it will be important to experimentally investigate possible mechanisms. Stewart et al. Samuels et al. often have a deteriorating respiratory chain function and may accumulate mutated mtDNA with time (Larsson et al. Maternal transmission of this apparently random set of point mutations generated in the mtDNA mutator mouse (Trifunovic et al. thus questioning the efficiency of this proposed mitochondrial quality control mechanism. It came as a true surprise when it was observed that the mtDNA genotype could shift completely in a few generations in cows (Olivo et al.. and results are also conflicting about whether there is a concomitant mtDNA copy number reduction in primordial germ cells (Cao et al. It is. These results suggest that the naturally occurring spectrum of mtDNA mutations in humans can be explained by mtDNA replication errors that have been subjected to purifying selection in the maternal germline. 2008a). A mechanism for selection at the level of the mtDNA is not easy to envision. exhibited a similar rapid.. 1983). 2008a. Wai et al. which is consistent with the observation that the majority of pathogenic mutations of human mtDNA affects tRNA genes. possible that a down-regulation of mtDNA copy number and fragmentation of the mitochondrial network may facilitate purifying selection in the maternal germline. The transmission of mtDNA mutations through the mouse maternal germline is not neutral. 2008).. The bottleneck mechanism may be linked to the purifying selection.. 1990). of on August 17. A more plausible mechanism is functional testing of mtDNA at the level of a single organelle (Shoubridge and Wai. germline segregation of mtDNA (Jenuth et al. by introducing pathogenic mtDNA mutations into mice concomitant with experimental manipulation of mtDNA copy number and mitochondrial dynamics in the female germline. the spectrum of mutations present in offspring to the mtDNA mutator mouse has clear similarities to the naturally occurring spectrum of mutations observed in human populations (Stewart et al. 2010). The molecular mechanism of purifying selection is not understood. Heteroplasmic mice containing mtDNA from two different mouse strains. 1980). although they only occupy 9% of the genome (Stewart et al.b). which leads to accumulation of high levels of acquired point mutations in mtDNA (Trifunovic et al. 2012 . whereby only a small fraction of all mtDNA copies in the primordial germ cell is transmitted to the oocyte.. Surprisingly.. 1974. such a selection could occur at different levels (Fig. 2008.. 2004).. The mtDNA mutator mouse expresses a catalytic subunit of Pol- with deficient proofreading capacity (Table I). but there is rather a strong purifying selection against deleterious mtDNA mutations (Fan et al.b). Repeated cell division will lead to mitotic segregation of normal and mutated mtDNA.  Mitotic segregation of mtDNA. and a particular mtDNA molecule may be replicated many times or not at all during a single cell cycle.. A single mutational event creates heteroplasmy in a cell. whereas mutations affecting tRNA or rRNA coding genes are better tolerated (Stewart et al.. 2007. It is also possible that there is a competition between cells during germ cell development and that cells with high levels of mutated mtDNA will be disfavored or undergo apoptosis. created by experimental manipulation of embryos.

but aging symptoms are not observed until early adult life. The results from the mtDNA mutator mouse thus lend some experimental support to the hypothesis that somatic mtDNA mutations created during embryogenesis may contribute to the creation of aging phenotypes in adult life..  Different levels at which purifying selection can occur in the maternal germline. Zeviani and Di Donato. 2008). and there is no evidence for increased oxidative stress (Kujoth et al. but the extent to which this aberration impairs organ function is unknown.. this study has been refuted in several independent studies. (middle) A fragmented mitochondrial network would allow functional testing of individual mtDNA molecules. 2009) or deep sequencing (Williams et al. Mosaic respiratory chain deficiency caused by clonal expansion of mtDNA mutations is ubiquitously observed in human aging. Interestingly. 2005). Ameur et al. Pathophysiological effects of mtDNA mutations Downloaded from jcb... and mouse models have therefore been developed by introducing naturally occurring mtDNA mutations into mouse embryos or by manipulating nuclear genes that control the maintenance and expression of mtDNA. 2010). It is important to emphasize that there is as yet no transfection system for mammalian mitochondria. 2001. There are indeed a large number of different types of mtDNA mutations that have effects on respiratory chain function and ATP synthesis (Larsson and Clayton. Furthermore. 2009. 2010. 2009). 2010). 2004). 2007. It is well established that somatic mtDNA mutations in human aging undergo clonal expansion and cause a mosaic respiratory chain dysfunction in different tissues (Krishnan et al. There has been one study arguing that a third type of mutation. It is important to emphasize that one should not expect fundamental differences in the pathophysiology of mtDNA mutations regardless of whether they occur in genetic syndromes or in aging. (top) Genomes with mutations could be blocked from replication or selectively destroyed without the need for gene expression.. It is important to remember that there are possibilities that mtDNA mutations could have effects unrelated to oxidative phosphorylation.. The role of somatic mtDNA mutations in mammalian aging has recently been extensively reviewed (Krishnan et al. drives the phenotype of mtDNA mutator mice (Vermulst et al. Mutations of mtDNA have several downstream effects that are a consequence of deficient oxidative phosphorylation. The mtDNA mutator mice (Table I) develop a premature aging syndrome. 2005.. and the most straightforward prediction is therefore that mtDNA mutations should have no other primary effects besides impairing cellular energy production.Published May 23. has on specialized functions of the affected cell. and only some issues will be discussed here. 1995. the point mutation load is high already during embryogenesis in mtDNA mutator mice.. mitotic segregation of heteroplasmic mtDNA mutations. 2009). the biochemical phenotype in mtDNA mutator mice is fully consistent with the idea that point mutations of mtDNA create amino acid substitutions of respiratory chain subunits. which likely represent a continuously formed replication intermediate (Trifunovic et al. 1998). Bailey et al. which. in turn. and respiratory chain– deficient (red) and normal (blue) cells (bottom). Larsson.. (bottom) Cells with high levels of mutated mtDNA may fail to compete with respiratory chain–competent cells and may be selected against or undergo apoptosis. circular mtDNA molecules with deletions. and those will be further discussed in the next on August 17. Munnich and Rustin. in which sensitive PCR assays (Edgar et al. Important principles in mitochondrial genetics. the consequence of an mtDNA mutation at the cellular level will not depend on whether the mtDNA mutation is spontaneous or acquired but will rather depend on the type of mtDNA mutation and how it impairs respiratory chain function and the consequences this impairment. which explains the observed decline in the stability of the respiratory chain complexes (Edgar et al. The presence of a mutated mtDNA molecule would result in a mitochondrion with deficient respiratory chain function. However. an alternative  814 JCB • VOLUME 193 • NUMBER 5 • 2011 The studies of pathophysiological effects of altered mtDNA expression have to a large extent been dependent on the use of mouse models (Table I). 2011) could not detect any significant levels of circular mtDNA molecules with deletions in various tissues of mtDNA mutator mice. In addition. e. 2012 Aging and somatic mtDNA mutations Patients with mitochondrial syndromes have a monoclonal expansion of mutated mtDNA leading to high levels of a single type of mutation.g. Kraytsberg et al. 2011 Figure 3. Trifunovic et al. 2010). However. 2007. It has generally been assumed that age-associated somatic mtDNA mutations are caused by accumulated damage during the aging process (Wallace. 2004. 2009. Expression of mtDNA is essential for oxidative phosphorylation (Larsson et al.. which is caused by the accumulation of point mutations and the presence of linear deleted mtDNA molecules. in turn.. 2001). respiratory chain–deficient (red) and normal (blue) mitochondria (middle). Amino acid replacements of mtDNA-encoded . Larsson... whereas aging is associated with polyclonal expansions leading to low levels of many different types of mtDNA mutations. are also applicable to aging. would lead to selection against and/or destruction of this mitochondrion. hypothesis is that most of the mutations are created as replication errors during embryogenesis and then undergo clonal expansion in adult life (Larsson. The colors indicate mutant (red) and wild-type (blue) mtDNA (top). Edgar et al.rupress..

2007). 2001). Hum. thus. Psychiatry.g. doi:10.T.22... but this concept has poor experimental support.. Downloaded from jcb.. which weeds out the most deleterious mutations. Ameur. Murphy. Stewart. W. J.O. Vilà. 2008) and age-related loss of muscle mass (Wenz et al. doi:10. 2009). Increased production of reactive oxygen species (ROS) and oxidative damage are heavily implicated in human pathology and aging. which allows rapid shifts of genotypes between generations. tissue-specific knockout mice with impaired mtDNA maintenance (Wang et al. Wredenberg et al. E. Hum.G. 2000). 2012 Submitted: 5 October 2010 Accepted: 7 March 2011 References Akman. Experiments in mice with mtDNA depletion in skeletal muscle have shown that activation of mitochondrial biogenesis at least partly can compensate for the deficient mitochondrial function and maintain close to normal overall ATP production in the affected tissue (Wredenberg et al. 2002). J. Leeuwenburgh. Science. Hagström. Larsson. Hänninen. Bruton. Also. Podowski. L. or impaired mitochondrial translation (Metodiev et al. 2009. a subsequent study showed that depletion of mtDNA caused by knockout of TFAM in the mouse leads to increased in vivo apoptosis (Wang et al.O.. 2009) have increased mitochondrial mass in affected tissues. U. doi:10. 1951. García-Cazorla. 2004). On the contrary.1093/hmg/ddn143 Allen. D. 1931. Genet. Mol.. Aydin et al. 1996). L. Wredenberg. and I. Similarly. and U. L. C.B. 2003. it has been reported that ROS production and oxidative damage are not increased in different tissues of mice with depletion (Wang et al.. 2009. Dauer.C. e. Larsson. However. but the role this type of damage plays is much debated (Bokov et al.L. Mol. doi:10.rupress. 2005. 1998. 2004. Patients with pathogenic mtDNA mutations often accumulate increased levels of mitochondria.M. 2010). N. S. deficient ATP production.C.... Selection of a mtDNA sequence variant in hepatocytes of heteroplasmic mice is not due to differences in respiratory chain function or efficiency of replication. pyramidal neurons (Sörensen et al. Hum. T. 2011). There is also evidence that mtDNA sequence variants may elicit an innate immune response against tumor cells (Ishikawa et al.R. Mice expressing an error-prone DNA polymerase in mitochondria display elevated replication pausing and chromosomal breakage at fragile sites of mitochondrial DNA.. Andersson. 2001. However. and Technology (grants 2010-0015769 and 2010-0001939). However. 18:278–288. P. J.M..G.A. Genet. Leigh. A. M. The different types of pathologies that are caused by mtDNA mutations are remarkable. It is often argued that mitochondrial dysfunction increases ROS production (Wallace.B.. 1990).G.J. 2001).F.. S... we have seen a remarkable increase in our understanding of mitochondrial genetics in mammals. and. The genome sequence of Rickettsia prowazekii and the origin of mitochondria. 2009b). T. R. A. manifested as ragged-red muscle fibers in skeletal muscle. on August 17.J. 1990. This controversy is to some extent explained by the complex chemistry of ROS formation (Murphy. Trifunovic et al. Park. Cluett. the underlying pathophysiology is not understood in any depth.1002/cfg.. dopamine neurons (Ekstrand et al. and pancreatic  cells (Silva et al.H. Ultra-deep sequencing of mouse mitochondrial DNA: mutational patterns and their origins. 2005. Nature. and in many cases there is a reasonably good correlation between genotype and phenotype. 1931. 2002).. Tanji. López. 1993). Prolla. Sicheritz-Pontén. Gyllensten. Andersson. 2009) and uncertainties about the performance of methods used to measure ROS (Bokov et al. It was initially reported that mtDNA is not required for execution of apoptosis in cell lines (Jacobson et al.1093/hmg/10. e. 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