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2. Neuromelanin, neurotransmitter status and brainstem location determine the differential vulnerability of catecholaminergic neurons to mitochondrial DNA deletions

Author

Elstner, Matthias, Müller, Sarina K, Leidolt, Lars, Laub, Christoph, Krieg, Lena, Schlaudraff, Falk, Liss, Birgit, Morris, Chris, Turnbull, Douglass M, Masliah, Eliezer, Prokisch, Holger, Klopstock, Thomas, and Bender, Andreas

Abstract

Abstract Background Deletions of the mitochondrial DNA (mtDNA) accumulate to high levels in dopaminergic neurons of the substantia nigra pars compacta (SNc) in normal aging and in patients with Parkinson's disease (PD). Human nigral neurons characteristically contain the pigment neuromelanin (NM), which is believed to alter the cellular redox-status. The impact of neuronal pigmentation, neurotransmitter status and brainstem location on the susceptibility to mtDNA damage remains unclear. We quantified mtDNA deletions (ΔmtDNA) in single pigmented and non-pigmented catecholaminergic, as well as non-catecholaminergic neurons of the human SNc, the ventral tegmental area (VTA) and the locus coeruleus (LC), using laser capture microdissection and single-cell real-time PCR. Results In healthy aged individuals, ΔmtDNA levels were highest in pigmented catecholaminergic neurons (25.2 ± 14.9%), followed by non-pigmented catecholamergic (18.0 ± 11.2%) and non-catecholaminergic neurons (12.3 ± 12.3%; p < 0.001). Within the catecholaminergic population, ΔmtDNA levels were highest in dopaminergic neurons of the SNc (33.9 ± 21.6%) followed by dopaminergic neurons of the VTA (21.9 ± 12.3%) and noradrenergic neurons of the LC (11.1 ± 11.4%; p < 0.001). In PD patients, there was a trend to an elevated mutation load in surviving non-pigmented nigral neurons (27.13 ± 16.73) compared to age-matched controls (19.15 ± 11.06; p = 0.052), but levels where similar in pigmented nigral neurons of PD patients (41.62 ± 19.61) and controls (41.80 ± 22.62). Conclusions Catecholaminergic brainstem neurons are differentially susceptible to mtDNA damage. Pigmented dopaminergic neurons of the SNc show the highest ΔmtDNA levels, possibly explaining the exceptional vulnerability of the nigro-striatal system in PD and aging. Although loss of pigmented noradrenergic LC neurons also is an early feature of PD pathology, mtDNA levels are not elevated in this nucleus in healthy controls. Thus, ΔmtDNA are neither an inevitable consequence of catecholamine metabolism nor a universal explanation for the regional vulnerability seen in PD.

Published
2011

4. Towards clinical application of pronuclear transfer to prevent mitochondrial DNA disease

Author

Hyslop, Louise A., Blakeley, Paul, Craven, Lyndsey, Richardson, Jessica, Fogarty, Norah M.E., Fragouli, Elpida, Lamb, Mahdi, Wamaitha, Sissy E., Prathalingam, Nilendran, Zhang, Qi, O'Keefe, Hannah, Takeda, Yuko, Arizzi, Lucia, Alfarawati, Samer, Tuppen, Helen A., Irving, Laura, Kalleas, Dimitrios, Choudhary, Meenakshi, Wells, Dagan, Murdoch, Alison P., Turnbull, Douglass M., Niakan, Kathy K., and Herbert, Mary

Subjects
Genetic engineering -- Innovations, Mitochondrial diseases -- Prevention, Mitochondrial DNA -- Properties, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Mitochondrial DNA (mtDNA) mutations are maternally inherited and are associated with a broad range of debilitating and fatal diseases (1). Reproductive technologies designed to uncouple the inheritance of mtDNA from nuclear DNA may enable affected women to have a genetically related child with a greatly reduced risk of mtDNA disease. Here we report the first preclinical studies on pronuclear transplantation (PNT). Surprisingly, techniques used in proof-of-concept studies involving abnormally fertilized human zygotes (2) were not well tolerated by normally fertilized zygotes. We have therefore developed an alternative approach based on transplanting pronuclei shortly after completion of meiosis rather than shortly before the first mitotic division. This promotes efficient development to the blastocyst stage with no detectable effect on aneuploidy or gene expression. After optimization, mtDNA carryover was reduced to, Predicting the risk of serious disease in children of women who carry mtDNA mutations is complicated by a number of factors. Mutations in mtDNA can be either homoplasmic (all copies [...]

Published
2016

7. Pronuclear transfer in human embryos to prevent transmission of mitochondrial DNA disease

Author

Craven, Lyndsey, Tuppen, Helen A., Greggains, Gareth D., Harbottle, Stephen J., Murphy, Julie L., Cree, Lynsey M., Murdoch, Alison P., Chinnery, Patrick F., Taylor, Robert W., Lightowlers, Robert N., Herbert, Mary, and Turnbull, Douglass M.

Subjects
Embryonic development -- Research -- Genetic aspects, Human embryo -- Research -- Genetic aspects, Disease transmission -- Prevention, Genotype -- Research, Mitochondrial DNA -- Research -- Physiological aspects -- Diseases, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Mutations in mitochondrial DNA (mtDNA) are a common cause of genetic disease. Pathogenic mutations in mtDNA are detected in approximately 1 in 250 live births (1-3) and at least 1 in 10,000 adults in the UK are affected by mtDNA disease (4). Treatment options for patients with mtDNA disease are extremely limited and are predominantly supportive in nature. Mitochondrial DNA is transmitted maternally and it has been proposed that nuclear transfer techniques may be an approach for the prevention of transmission of human mtDNA disease (5,6). Here we show that transfer of pronuclei between abnormally fertilized human zygotes results in minimal carry-over of donor zygote mtDNA and is compatible with onward development to the blastocyst stage in vitro. By optimizing the procedure we found the average level of carry-over after transfer of two pronuclei is less than 2.0%, with many of the embryos containing no detectable donor mtDNA. We believe that pronuclear transfer between zygotes, as well as the recently described metaphase II spindle transfer, has the potential to prevent the transmission of mtDNA disease in humans., Mitochondrial DNA is present in all cells in multiple copies. Mutations in it are maternally transmitted7. In patients with mtDNA disease, either all mtDNA copies are mutated (homoplasmy) or there [...]

Published
2010
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8. Mutations in the SPG7 gene cause chronic progressive external ophthalmoplegia through disordered mitochondrial DNA maintenance

Author

Pfeffer, Gerald, Gorman, Gráinne S, Griffin, Helen, Kurzawa-Akanbi, Marzena, Blakely, Emma L., Wilson, Ian, Sitarz, Kamil, Moore, David, Murphy, Julie L., Alston, Charlotte L., Pyle, Angela, Coxhead, Jon, Payne, Brendan, Gorrie, George H., Longman, Cheryl, Hadjivassiliou, Marios, McConville, John, Dick, David, Imam, Ibrahim, Hilton, David, Norwood, Fiona, Baker, Mark R., Jaiser, Stephan R., Yu-Wai-Man, Patrick, Farrell, Michael, McCarthy, Allan, Lynch, Timothy, McFarland, Robert, Schaefer, Andrew M., Turnbull, Douglass M., Horvath, Rita, Taylor, Robert W., and Chinnery, Patrick F.

Published
2014
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12. Mutant POLG2 disrupts DNA polymerase gama subunits and causes progressive external opthalmoplegia

Author

Longley, Matthew J., Clark, Susanna, Cynthia Yu Wai Man, Hudson, Gavin, Durham, Steve E., Taylor, Robert W., Nightingale, Simon, Turnbull, Douglass M., Copeland, William C., and Chinnery, Patrick F.

Subjects
Biological sciences
Abstract

A heterozygous dominant mutation in POLG2 is described, the gene encoding the p55 accessory subunit of pol gama, that causes progressive external opthalmoplegia with multiple mtDNA deletions and cytochrome c oxidase-(COX) deficient muscle fibres. The progressive accumulation of mtDNA deletions causes COX deficiency in muscle fibres and results in the clinical phenotype.

Published
2006

16. Adults with RRM2B-related mitochondrial disease have distinct clinical and molecular characteristics

Author

Pitceathly, Robert D. S., Smith, Conrad, Fratter, Carl, Alston, Charlotte L., He, Langping, Craig, Kate, Blakely, Emma L., Evans, Julie C., Taylor, John, Shabbir, Zarfishan, Deschauer, Marcus, Pohl, Ute, Roberts, Mark E., Jackson, Matthew C., Halfpenny, Christopher A., Turnpenny, Peter D., Lunt, Peter W., Hanna, Michael G., Schaefer, Andrew M., McFarland, Robert, Horvath, Rita, Chinnery, Patrick F., Turnbull, Douglass M., Poulton, Joanna, Taylor, Robert W., and Gorman, Gráinne S.

Published
2012
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18. GRACILE syndrome, a lethal metabolic disorder with iron overload, is caused by a point mutation in BCS1L

Author

Visapaa, Ilona, Fellman, Vineta, Vesa, Jouni, Dasvarma, Ayan, Hutton, Jenna L., Kumar, Vijay, Payne, Gregory S., Makarow, Marja, Van Coster, Rudy, Taylor, Robert W., Turnbull, Douglass M., Suomalainen, Anu, and Peltonen, Leena

Subjects
Human genetics, Metabolic diseases -- Research, Metabolic diseases -- Genetic aspects, Metabolic diseases -- Health aspects, Metabolic diseases -- Demographic aspects, Dwarfism -- Genetic aspects, Dwarfism -- Causes of, Dwarfism -- Demographic aspects, Cholestasis -- Genetic aspects, Cholestasis -- Causes of, Cholestasis -- Demographic aspects, Jaundice, Obstructive, Gene expression -- Physiological aspects, Proteins -- Genetic aspects, Mitochondrial DNA -- Genetic aspects, Biological sciences
Published
2002

23. An mtDNA mutation in the initiation codon of the cytochrome C oxidase subunit II gene results in lower levels of the protein and a mitochondrial encephalomyopathy

Author

Clark, Kim M., Taylor, Robert W., Johnson, Margaret A., Chinnery, Patrick F., Chrzanowska-Lightowlers, Zofia M.A., Andrews, Richard M., Nelson, Isobel P., Wood, Nicholas W., Lamont, Phillipa J., Hanna, Michael G., Lightowlers, Robert N., and Turnbull, Douglass M.

Subjects
Genetic disorders -- Research, Chromosome mapping -- Usage, Mitochondrial DNA -- Physiological aspects, Mitochondrial myopathies -- Genetic aspects, Encephalopathy -- Genetic aspects, Biological sciences
Abstract

A family with mitochondrial disease was found to have an mtDNA mutation in the initiation codon of the cytochrome C oxidase subunit II (COX II) gene. The mutation brings lower levels of the protein and a mitochondrial encephalomyopathy. It is predicted that the T-->C transition changes the initiating methionine to threonine. The mutation load was at 67% in muscle from the index case and at 91% in muscle from the clinically affected son of the patient. An isolated COX deficiency was seen in muscle biopsy samples. The mutation is a new mechanism through which mtDNA mutations can cause disease-defective translation initiation.

Published
1999

25. Naked mole-rats maintain healthy skeletal muscle and Complex IV mitochondrial enzyme function into old age

Author

Stoll, Elizabeth A, Karapavlovic, Nevena, Rosa, Hannah, Woodmass, Michael, Rygiel, Karolina, White, Kathryn, Turnbull, Douglass M, and Faulkes, Chris G

Subjects
Male, Aging, Electron Transport Complex I, naked mole-rat, Mole Rats, mitochondria, sarcopenia, Electron Transport Complex IV, Muscular Atrophy, oxidative stress, animal models of aging, Animals, Muscle, Skeletal, Research Paper
Abstract

The naked mole-rat (NMR) Heterocephalus glaber is an exceptionally long-lived rodent, living up to 32 years in captivity. This extended lifespan is accompanied by a phenotype of negligible senescence, a phenomenon of very slow changes in the expected physiological characteristics with age. One of the many consequences of normal aging in mammals is the devastating and progressive loss of skeletal muscle, termed sarcopenia, caused in part by respiratory enzyme dysfunction within the mitochondria of skeletal muscle fibers. Here we report that NMRs avoid sarcopenia for decades. Muscle fiber integrity and mitochondrial ultrastructure are largely maintained in aged animals. While mitochondrial Complex IV expression and activity remains stable, Complex I expression is significantly decreased. We show that aged naked mole-rat skeletal muscle tissue contains some mitochondrial DNA rearrangements, although the common mitochondrial DNA deletions associated with aging in human and other rodent skeletal muscles are not present. Interestingly, NMR skeletal muscle fibers demonstrate a significant increase in mitochondrial DNA copy number. These results have intriguing implications for the role of mitochondria in aging, suggesting Complex IV, but not Complex I, function is maintained in the long-lived naked mole rat, where sarcopenia is avoided and healthy muscle function is maintained for decades.

Published
2016

29. Assessing mitochondrial heteroplasmy using next generation sequencing: A note of caution

Author

Santibanez-Koref, Mauro, Griffin, Helen, Turnbull, Douglass M., Chinnery, Patrick F., Herbert, Mary, and Hudson, Gavin

Subjects
Mitochondrial Diseases, Computational Biology, Genetic Variation, High-Throughput Nucleotide Sequencing, Humans, Sequence Analysis, DNA, DNA, Mitochondrial, Article
Abstract

The mitochondrial genome has recently become the focus of several high-impact next-generation sequencing studies investigating the effect of mutations in disease and assessing the efficacy of mitochondrial replacement therapies. However, these studies have failed to take into consideration the capture of recurring translocations of mitochondrial DNA to the nuclear genome, known as nuclear mitochondrial sequences (NUMTs), continuing to align sequence data to the revised Cambridge reference sequence alone. Here, using different mtDNA enrichment techniques and a variety of tissues, we demonstrate that NUMTs are present in sequence data and that, dependent upon downstream analysis, are at a level which affects variant calling.

Published
2019

36. Mitochondrial DNA mutations in human colonic crypt stem cells

Author

Taylor, Robert W., Barron, Martin J., Borthwick, Gillian M., Gospel, Amy, Chinnery, Patrick F., Samuels, David C., Taylor, Geoffrey A., Plusa, Stefan M., Needham, Stephanie J., Greaves, Laura C., Kirkwood, Thomas B.L., and Turnbull, Douglass M.

Published
2003

45. Mitochondrial DNA Transcription: Regulating the Power Supply

Author

Taylor, Robert W. and Turnbull, Douglass M.

Subjects
Mitochondrial DNA, Biological sciences
Abstract

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.cell.2007.07.002 Byline: Robert W. Taylor (1)(2), Douglass M. Turnbull (1)(2)(3) Abstract: In this issue of Cell, describe the nuclear encoded protein MTERF3 as a negative regulator of mitochondrial DNA transcription initiation. This study highlights a mechanism by which mitochondrial DNA transcription (and therefore oxidative phosphorylation) may be regulated in response to alterations in the cell's physiological and metabolic demands. Author Affiliation: (1) Mitochondrial Research Group, School of Neurology, Neurobiology and Psychiatry, The Medical School, Newcastle University, Newcastle upon Tyne, UK (2) Institute of Human Genetics, Newcastle University, Newcastle upon Tyne, UK (3) Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, UK

Published
2007

46. Sub-cellular origin of mtDNA deletions in human skeletal muscle

Author

Vincent, Amy E., Rosa, Hannah S., Pabis, Kamil, Lawless, Conor, Chen, Chun, Grunewald, Anne, Rygiel, Karolina A., Rocha, Mariana C., Reeve, Amy K., Falkous, Gavin, Perissi, Vanessa, White, Kathryn, Davey, Tracey, Petrof, Basil J., Sayer, Avan Aihie, Cooper, Cyrus, Deehan, David, Taylor, Robert W., Turnbull, Douglass M., and Picard, Martin

Published
2018

47. Opening One's Eyes to Mosaicism in Progressive External Ophthalmoplegia

Author

Sommerville, Ewen W., Jones, Rachel L., Hardy, Steven A., Blakely, Emma L., Pyle, Angela, Schaefer, Andrew M., Chinnery, Patrick F., Turnbull, Douglass M., Gorman, Gráinne S., Taylor, Robert W., Chinnery, Patrick [0000-0002-7065-6617], and Apollo - University of Cambridge Repository

Subjects
3209 Neurosciences, 32 Biomedical and Clinical Sciences, Clinical/Scientific Notes, 3202 Clinical Sciences, 3105 Genetics, 31 Biological Sciences
Published
2018
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48. Impact of age-related mitochondrial dysfunction and exercise on intestinal microbiota composition

Author

Houghton, David, Stewart, Christopher J, Stamp, Craig, Nelson, Andrew, Aj ami, Nadim J, Petrosino, Joseph F, Wipat, Anil, Trenell, Michael I, Turnbull, Douglass M, and Greaves, Laura C

Subjects
Aging, Mitochondrial Diseases, C100, A100, D300, Articles, Gut microbiota, C500, B400, C700, digestive system, Mitochondria, Gastrointestinal Microbiome, Feces, Mice, Random Allocation, Physical Conditioning, Animal, The Journal of Gerontology: Biological Sciences, COX deficiency, Animals, Sedentary Behavior, Exercise
Abstract

Mitochondrial dysfunction is prevalent in the aging gastrointestinal tract. We investigated whether mitochondrial function in aging colonic crypts and exercise influences microbial gut communities in mice. Twelve PolgAmut/mut mice were randomly divided into a sedentary and exercise group at 4 months. Seven-aged matched PolgA+/+ mice remained sedentary throughout. Stool samples were collected at 4, 7, and 11 months, and bacterial profiling was achieved through 16S rRNA sequencing profiling. Mitochondrial enzyme activity was assessed in colonic epithelial crypts at 11 months for PolgAmut/mut and PolgA+/+ mice. Sedentary and exercised PolgAmut/mut mice had significantly higher levels of mitochondrial dysfunction than PolgA+/+ mice (78%, 77%, and 1% of crypts, respectively). Bacterial profiles of sedentary PolgAmut/mut mice were significantly different from the sedentary PolgA+/+ mice, with increases in Lactobacillus and Mycoplasma, and decreases in Alistipes, Odoribacter, Anaeroplasma, Rikenella, Parabacteroides, and Allobaculum in the PolgAmut/mut mice. Exercise did not have any impact upon gut mitochondrial dysfunction; however, exercise did increase gut microbiota diversity and significantly increased bacterial genera Mucispirillum and Desulfovibrio. Mitochondrial dysfunction is associated with changes in the gut microbiota. Endurance exercise moderated some of these changes, establishing that environmental factors can influence gut microbiota, despite mitochondrial dysfunction.

Published
2018

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