Mitochondrial DNA mutations and human disease

In the paper

“Currently, more than 250 pathogenic mtDNA mutations have been identified.”

• Also stated in: § 3. Clinical features of human mtDNA disease · plain

  “Since then, over 250 pathogenic mtDNA mutations (point mutations and rearrangements) have been characterised [56]”

What the sources say

• Not checked yetcites [56] MITOMAP: A Human Mitochondrial Genome Database. http://www.mitomap.org. 2009.

In the paper

“The onset of clinical symptoms, phenotypic variability, and variable penetrance of mitochondrial diseases are governed by a number of factors, including the threshold effect, mitotic segregation, clonal expansion, and a genetic bottleneck.”

In the paper

“they are not sufficient to counteract the oxidative damage sustained by the mitochondrial genome due to its proximity to the RC complexes in the IMM and the ROS they generate.Protective histones are also lacking.”

In the paper

“Although the threshold level can partly explain the disease phenotypes observed in patients, an exact correlation between clinical severity and the proportion of mtDNA mutation is lacking [62].”

What the sources say

• Not checked yetcites [62] Wong, 2007, Diagnostic challenges of mitochondrial DNA disorders, Mitochondrion source

In the paper

“Clonal expansion refers to the preferential amplification of mtDNA mutations to a high level in post-mitotic tissues [64,65].”

What the sources say

• Not checked yetcites [64] Larsson, 1990, Progressive increase of the mutated mitochondrial DNA fraction in Kearns–Sayre syndrome, Pediatr. Res. source
• Not checked yetcites [65] Weber, 1997, A new mtDNA mutation showing accumulation with time and restriction to skeletal muscle, Am. J. Hum. Genet.

In the paper

“CPEO is typically caused by sporadic large-scale single deletions or multiple mtDNA deletions [119,120], although mtDNA point mutations are detected in some patients (e.g., m.3243A N G [121], m.12316G N A [122]).”

What the sources say

• Not checked yetcites [119] Moraes, 1989, Mitochondrial DNA deletions in progressive external ophthalmoplegia and Kearns–Sayre syndrome, N. Engl. J. Med. source
• Not checked yetcites [120] Van Goethem, 2003, Progressive external ophthalmoplegia characterized by multiple deletions of mitochondrial DNA: unraveling the pathogenesis of human mitochondrial DNA instability and the initiation of a genetic classification, Neuromol. Med. source
• Not checked yetcites [121] Moraes, 1993, Atypical clinical presentations associated with the MELAS mutation at position 3243 of human mitochondrial DNA, Neuromuscul. Disord. source
• Not checked yetcites [122] Cardaioli, 2008, Chronic progressive external ophthalmoplegia: a new heteroplasmic tRNA(Leu(CUN)) mutation of mitochondrial DNA, J. Neurol. Sci. source

In the paper

“Single mtDNA deletions occur sporadically early in development, and the identical deletion is present in all cells within affected tissues [87].”

What the sources say

• Not checked yetcites [87] Chen, 1995, Rearranged mitochondrial genomes are present in human oocytes, Am. J. Hum. Genet.

In the paper

“Leigh syndrome is due to severe failure of oxidative metabolism and can be due to a variety of different genetic defects affecting either the mitochondrial (e.g., m.8993T N C/G, m.10158T N C, m.10191T N C) or nuclear genome (e.g., SURF1 gene) [105].”

What the sources say

• Not checked yetcites [105] Finsterer, 2008, Leigh and Leigh-like syndrome in children and adults, Pediatr. Neurol. source

In the paper

“They mainly occur between the origins of replication, O H and O L , and are typically flanked by short direct repeats [94,95].”

What the sources say

• Not checked yetcites [94] Bua, 2006, Mitochondrial DNA-deletion mutations accumulate intracellularly to detrimental levels in aged human skeletal muscle fibers, Am. J. Hum. Genet. source
• Not checked yetcites [95] Samuels, 2004, Two direct repeats cause most human mtDNA deletions, Trends Genet. source

In the paper

“The majority of mtDNA rearrangement mutations are large-scale deletions, which vary in size from 1.3 to 8 kb and span several genes [86].”

What the sources say

• Not checked yetcites [86] Schon, 1989, A direct repeat is a hotspot for large-scale deletion of human mitochondrial DNA, Science source

In the paper

“Whilst cybrids and yeast have helped to further our current understanding of mitochondrial genetics and the molecular mechanisms of disease, a mammalian in vivo model system is ultimately necessary for answering the many questions regarding mtDNA biology, mitochondrial disease pathogenesis and tissue specificity that still remain.”

In the paper

“In addition, these cell models have challenged our established criteria for pathogenicity with the identification of the first mt-tRNA suppressor mutation, m.12300G N A in MT-L2 [154], and the first functionally dominant mt-tRNA mutation, m.5545C N T in MT-TW [155].”

What the sources say

• Not checked yetcites [154] El Meziane, 1998, A tRNA suppressor mutation in human mitochondria, Nat. Genet. source
• Not checked yetcites [155] Khan, 2007, Cell and animal models of mtDNA biology: progress and prospects, Am. J. Physiol., Cell Physiol. source

In the paper

“A global decrease in the activity of COX is usually suggestive of a nuclear mutation in an ancillary protein required for COX assembly such as SURF1 but can be associated with some homoplasmic mt-tRNA defects [77,78].”

What the sources say

• Not checked yetcites [77] McFarland, 2002, Multiple neonatal deaths due to a homoplasmic mitochondrial DNA mutation, Nat. Genet. source
• Not checked yetcites [78] Taylor, 2003, A homoplasmic mitochondrial transfer ribonucleic acid mutation as a cause of maternally inherited hypertrophic cardiomyopathy, J. Am. Coll. Cardiol. source

In the paper

“The assessment of m.3243A N G mutation load in urinary sediments not only provides a correlate with the level in muscle but also has proven to be an accurate indicator of clinical outcome for these patients [138].”

What the sources say

• Not checked yetcites [138] Whittaker, 2009, Urine heteroplasmy is the best predictor of clinical outcome in the m.3243A>G mtDNA mutation, Neurology source

In the paper

“By allowing selected mtDNA sequences to be expressed against fixed nuclear backgrounds, not only can cybrids be employed for establishing and/or confirming the genetic origin of a mitochondrial disorder, but they can also provide a controlled environment in which to study both the functional and physiological consequences of varying levels of heteroplasmy of specific mtDNA mutations as well as the”

In the paper

“Consequently, it is unlikely that a reduced respiration rate is solely responsible for this variability, but rather additional molecular mechanisms must also contribute to the development and clinical presentation of disease.”

In the paper

“Most importantly, this can be achieved in a highly controlled fashion as DNA delivered to mitochondria via biolistic transformation can only incorporate into the mitochondrial genome by homologous recombination [160].”

What the sources say

• Not checked yetcites [160] Bonnefoy, 2001, Genetic transformation of Saccharomyces cerevisiae mitochondria, Methods Cell Biol. source

In the paper

“However, the introduction over the past decade of an alternative model, the obligate aerobic yeast Yarrowia lipolytica, which possesses a vital proton-pumping NADH:ubiquinone oxidoreductase, has enabled important structural and functional analyses of mitochondrial complex I [168].”

What the sources say

• Not checked yetcites [168] Kerscher, 2004, Application of the yeast Yarrowia lipolytica as a model to analyse human pathogenic mutations in mitochondrial complex I (NADH:ubiquinone oxidoreductase), Biochim. Biophys. Acta source

In the paper

“Additional transmitochondrial mouse models, showing signs of mitochondrial dysfunction and capable of transmitting mtDNA mutations to subsequent generations, have since been established, including the 'Mito-mice' model that harbours high levels of a single heteroplasmic mtDNA deletion and shows a multitude of symptoms including myopathy, cardiomyopathy, renal failure, anaemia, deafness, lactic”

What the sources say

• Not checked yetcites [172] Inoue, 2000, Generation of mice with mitochondrial dysfunction by introducing mouse mtDNA carrying a deletion into zygotes, Nat. Genet. source
• Not checked yetcites [173] Nakada, 2004, Accumulation of pathogenic DeltamtDNA induced deafness but not diabetic phenotypes in mito-mice, Biochem. Biophys. Res. Commun. source

In the paper

“Also, S. cerevisiae are inherently homoplasmic, thus precluding threshold studies, although it is possible to modulate the severity of yeast respiratory phenotypes by studying mt-tRNA mutations in different nuclear contexts [163,164].”

What the sources say

• Not checked yetcites [163] De Luca, 2006, Mutations in yeast mt tRNAs: specific and general suppression by nuclear encoded tRNA interactors, Gene source
• Not checked yetcites [164] Montanari, 2008, Yeast as a model of human mitochondrial tRNA base substitutions: investigation of the molecular basis of respiratory defects, Rna source

In the paper

“The progression of the disease seems to depend upon the responsible mutation with 71% of patients with the m.14484T N C mutation showing some recovery, compared to 25% with m.11778G N A [125].”

What the sources say

• Not checked yetcites [125] Riordan-Eva, 1995, The clinical features of Leber's hereditary optic neuropathy defined by the presence of a pathogenic mitochondrial DNA mutation, Brain source

In the paper

“For example, cybrids harbouring the homoplasmic MT-TV m.1624C N T mutation, which caused a profound metabolic defect in skeletal and cardiac muscle, with low complex I and IV activities, and resulted in multiple neonatal deaths [159], were found to lack the marked respiratory defect despite retaining a striking reduction in mt-tRNA Val steady-state levels [159].”

What the sources say

• Not checked yetcites [159] Rorbach, 2008, Overexpression of human mitochondrial valyl tRNA synthetase can partially restore levels of cognate mt-tRNAVal carrying the pathogenic C25U mutation, Nucleic Acids Res. source

In the paper

“Increased ROS production has been described in neuronal NT2 cybrid cells containing m.3460G N A and m.11778G N A LHON mutations [187], in lymphocytes with m.8993T N C and m.8993T N G NARP mutations [188] and more recently in the chimeric m.3243A N G mice mentioned previously [175].”

What the sources say

• Not checked yetcites [187] Wong, 2002, Differentiation-specific effects of LHON mutations introduced into neuronal NT2 cells, Hum. Mol. Genet. source
• Not checked yetcites [188] Baracca, 2007, Biochemical phenotypes associated with the mitochondrial ATP6 gene mutations at nt8993, Biochim. Biophys. Acta source
• Not checked yetcites [175] Li, 2008, Increased ROS generation and SOD activity in heteroplasmic tissues of transmitochondrial mice with A3243G mitochondrial DNA mutation, Genet. Mol. Res. source

In the paper

“Conversely, normal levels of ROS were measured in the POLG1 mutator mice, which eventually accumulate sufficient mtDNA mutations to cause severe OXPHOS deficiency [189].”

What the sources say

• Not checked yetcites [189] Trifunovic, 2005, Somatic mtDNA mutations cause aging phenotypes without affecting reactive oxygen species production, Proc. Natl. Acad. Sci. U. S. A. source

In the paper

“Biochemical effects of mtDNA mutations have been well described in all experimental systems and are invariably characterised by lower cellular respiration, compromised RC complex activity, and reduced ATP synthesis.”

In the paper

“and the mt-tRNA Tyr m.5874T N C and m.5877C N T transitions [204].”

What the sources say

• Not checked yetcites [204] Bonnefond, 2008, Decreased aminoacylation in pathology-related mutants of mitochondrial tRNATyr is associated with structural perturbations in tRNA architecture, RNA source

In the paper

“Furthermore, no increase in programmed cell death was identified in this mouse model, contrary to a double TFAM knockout mouse model in which substantial apoptosis occurred at embryonic day 9.5 [179,190].”

What the sources say

• Not checked yetcites [179] Wang, 1999, Dilated cardiomyopathy and atrioventricular conduction blocks induced by heart-specific inactivation of mitochondrial DNA gene expression, Nat. Genet. source
• Not checked yetcites [190] Wang, 2001, Increased in vivo apoptosis in cells lacking mitochondrial DNA gene expression, Proc. Natl. Acad. Sci. U. S. A. source

In the paper

“However, although PNAs colocalised to mitochondria in intact cells, they were not able to cross the IMM.”

What the sources say

• Not checked yetcites [234] Taylor, 1997, Selective inhibition of mutant human mitochondrial DNA replication in vitro by peptide nucleic acids, Nat. Genet. source

In the paper

“Other shared transcriptional consequences of mitochondrial dysfunction include inhibition of both ubiquitin-mediated protein degradation and mitochondrial and nuclear ribosomal protein synthesis [214,215], as well as activation of the unfolded protein response [215,216].”

What the sources say

• Not checked yetcites [214] Jahangir Tafrechi, 2005, Distinct nuclear gene expression profiles in cells with mtDNA depletion and homoplasmic A3243G mutation, Mutat. Res. source
• Not checked yetcites [215] Alemi, 2007, Mitochondrial DNA deletions inhibit proteasomal activity and stimulate an autophagic transcript, Free Radic. Biol. Med. source
• Not checked yetcites [216] Cortopassi, 2006, Mitochondrial disease activates transcripts of the unfolded protein response and cell cycle and inhibits vesicular secretion and oligodendrocyte-specific transcripts, Mitochondrion source

In the paper

“Moreover, the nature of the mtDNA mutations, in particular the m.9205delTA deletion, which eliminates the MT-ATP6 gene stop codon, placing MT-CO3 immediately in frame, and causes a marked decrease in RNA14 (MT-ATP8 and -6-encoding bicistronic transcript) steady-state levels [81]”

What the sources say

• Not checked yetcites [81] Temperley, 2003, Investigation of a pathogenic mtDNA microdeletion reveals a translation-dependent deadenylation decay pathway in human mitochondria, Hum. Mol. Genet. source

In the paper

“Muscle conditioning enhanced ATP levels, delayed disease onset, and increased life expectancy in these mice.”

What the sources say

• Not checked yetcites [231] Wenz, 2009, Endurance exercise is protective for mice with mitochondrial myopathy, J. Appl. Physiol. source

In the paper

“Well tolerated and safe, endurance training for up to 14 weeks has been found to improve OXPHOS function, although no concomitant shift in mutated mtDNA levels in muscle has been observed and cessation in training does cause a loss of the physiological adaptations [228][229][230].”

What the sources say

• Not checked yetcites [228] Taivassalo, 2005, Exercise and training in mitochondrial myopathies, Med. Sci. Sports Exerc. source
• Not checked yetcites [229] Jeppesen, 2006, Aerobic training is safe and improves exercise capacity in patients with mitochondrial myopathy, Brain source
• Not checked yetcites [230] Taivassalo, 2006, Endurance training and detraining in mitochondrial myopathies due to single large-scale mtDNA deletions, Brain source

In the paper

“Imported tRNA Lys molecules are correctly aminoacylated, able to participate in mitochondrial translation, and partially rescue mitochondrial functions [242].”

What the sources say

• Not checked yetcites [242] Kolesnikova, 2004, Nuclear DNA-encoded tRNAs targeted into mitochondria can rescue a mitochondrial DNA mutation associated with the MERRF syndrome in cultured human cells, Hum. Mol. Genet. source

In the paper

“The most recent mammalian mitochondrial compendium (MitoCarta) consists of 1098 identified proteins [209].”

What the sources say

• Not checked yetcites [209] Pagliarini, 2008, A mitochondrial protein compendium elucidates complex I disease biology, Cell source

In the paper

“Furthermore, two recent studies have demonstrated an increase in mutant mt-tRNA Val [159] and mt-tRNA Leu(UUR) [166] steady-state levels following overexpression of the valyl and leucyl synthetases, respectively.”

What the sources say

• Not checked yetcites [159] Rorbach, 2008, Overexpression of human mitochondrial valyl tRNA synthetase can partially restore levels of cognate mt-tRNAVal carrying the pathogenic C25U mutation, Nucleic Acids Res. source
• Not checked yetcites [166] Park, 2008, Overexpressed mitochondrial leucyl-tRNA synthetase suppresses the A3243G mutation in the mitochondrial tRNA(Leu(UUR)) gene, Rna source

In the paper

“Twelve-week resistance training studies in patients with single, large-scale mtDNA deletions have been demonstrated to increase satellite cell number with concomitant improvements in muscular strength and oxidative capacity evidenced by a decrease in the proportion of COX-negative fibres [233].”

What the sources say

• Not checked yetcites [233] Murphy, 2008, Resistance training in patients with single, large-scale deletions of mitochondrial DNA, Brain source

In the paper

“Indeed, AOX was well tolerated and transfectants displayed remarkable levels of cyanide resistance to mitochondrial metabolite oxidation.”

What the sources say

• Not checked yetcites [247] Hakkaart, 2006, Allotopic expression of a mitochondrial alternative oxidase confers cyanide resistance to human cell respiration, EMBO Rep. source

In the paper

“However, studies in heteroplasmic mice have demonstrated almost identical levels of heteroplasmy between the ooplasm and polar body of the mature oocyte and also between individual blastomeres [250].”

What the sources say

• Not checked yetcites [250] Dean, 2003, Prospect of preimplantation genetic diagnosis for heritable mitochondrial DNA diseases, Mol. Hum. Reprod. source

In the paper

“An alternative approach involving pronuclear transfer, the transfer of the pronuclei from a fertilised zygote of a mother with mtDNA disease to an enucleated zygote from a healthy donor female, is presently being investigated in abnormally fertilised human embryos (Turnbull et al., unpublished data).”

What the sources say

• Not checked yetcites Turnbull et al., unpublished data

In the paper

“Recently, spindle-chromosome complex transfer from a mature primate oocyte to an enucleated primate egg successfully produced healthy offspring, in which, importantly, spindle donor mtDNA was not detected [252].”

What the sources say

• Not checked yetcites [252] Tachibana, 2009, Mitochondrial gene replacement in primate offspring and embryonic stem cells, Nature source

In the paper

“Furthermore, an encouraging strategy for the potential rescue of mitochondrial COX defects may soon be possible following the successful transfection and IMM targeting in human cultured cells of the sea squirt Ciona intestinalis cyanide-insensitive alternative oxidase (AOX) [247].”

What the sources say

• Not checked yetcites [247] Hakkaart, 2006, Allotopic expression of a mitochondrial alternative oxidase confers cyanide resistance to human cell respiration, EMBO Rep. source

In the paper

“Similarly, xenotopic expression of the green alga Chlamydomonas reinhardtii ATPase 6 (CrATP6) in human cybrid cells harbouring the m.8993T N G mutation resulted in moderately improved ATP production whilst cellular viability was fully recovered [246].”

What the sources say

• Not checked yetcites [246] Ojaimi, 2002, An algal nucleus-encoded subunit of mitochondrial ATP synthase rescues a defect in the analogous human mitochondrial-encoded subunit, Mol. Biol. Cell source