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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

6. 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

9. Defining cardiac adaptations and safety of endurance training in patients with m.3243A>G-related mitochondrial disease

Author

Bates, Matthew G.D., Newman, Jane H., Jakovljevic, Djordje G., Hollingsworth, Kieren G., Alston, Charlotte L., Zalewski, Pawel, Klawe, Jacek J., Blamire, Andrew M., MacGowan, Guy A., Keavney, Bernard D., Bourke, John P., Schaefer, Andrew, McFarland, Robert, Newton, Julia L., Turnbull, Douglass M., Taylor, Robert W., Trenell, Michael I., and Gorman, Gráinne S.

Published
2013
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19. 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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20. Use of Whole-Exome Sequencing to Determine the Genetic Basis of Multiple Mitochondrial Respiratory Chain Complex Deficiencies

Author

Taylor, Robert W., Pyle, Angela, Griffin, Helen, Blakely, Emma L., Duff, Jennifer, He, Langping, Smertenko, Tania, Alston, Charlotte L., Neeve, Vivienne C., Best, Andrew, Yarham, John W., Kirschner, Janbernd, Schara, Ulrike, Talim, Beril, Topaloglu, Haluk, Baric, Ivo, Holinski-Feder, Elke, Abicht, Angela, Czermin, Birgit, Kleinle, Stephanie, Morris, Andrew A. M., Vassallo, Grace, Gorman, Grainne S., Ramesh, Venkateswaran, Turnbull, Douglass M., Santibanez-Koref, Mauro, McFarland, Robert, Horvath, Rita, and Chinnery, Patrick F.

Published
2014
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21. 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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23. Pathogenic Mitochondrial tRNA Point Mutations: Nine Novel Mutations Affirm Their Importance as a Cause of Mitochondrial Disease

Author

Blakely, Emma L., Yarham, John W., Alston, Charlotte L., Craig, Kate, Poulton, Joanna, Brierley, Charlotte, Park, Soo-Mi, Dean, Andrew, Xuereb, John H., Anderson, Kirstie N., Compston, Alistair, Allen, Chris, Sharif, Saba, Enevoldson, Peter, Wilson, Martin, Hammans, Simon R., Turnbull, Douglass M., McFarland, Robert, and Taylor, Robert W.

Published
2013
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24. Does impaired mitochondrial function affect insulin signaling and action in cultured human skeletal muscle cells?

Author

Brown, Audrey E., Elstner, Matthias, Yeaman, Stephen J., Turnbull, Douglass M., and Walker, Mark

Subjects
Mitochondria -- Properties, Insulin -- Properties, Cellular signal transduction -- Evaluation, Muscles -- Properties, Physiological research, Biological sciences
Abstract

Insulin-resistant type 2 diabetic patients have been reported to have impaired skeletal muscle mitochondrial respiratory function. A key question is whether decreased mitochondrial respiration contributes directly to the decreased insulin action. To address this, a model of impaired cellular respiratory function was established by incubating human skeletal muscle cell cultures with the mitochondrial inhibitor sodium azide and examining the effects on insulin action. Incubation of human skeletal muscle cells with 50 and 75 [micro]M azide resulted in 48 [+ or -] 3% and 56 [+ or -] 1% decreases, respectively, in respiration compared with untreated cells mimicking the level of impairment seen in type 2 diabetes. Under conditions of decreased respiratory chain function, insulin-independent (basal) glucose uptake was significantly increased. Basal glucose uptake was 325 [+ or -] 39 pmol/min/mg (mean [+ or -] SE) in untreated cells. This increased to 669 [+ or -] 69 and 823 [+ or -] 83 pmol/min/mg in cells treated with 50 and 75 [micro]M azide, respectively (vs. untreated, both P < 0.0001). Azide treatment was also accompanied by an increase in basal glycogen synthesis and phosphorylation of AMP-activated protein kinase. However, there was no decrease in glucose uptake following insulin exposure, and insulin-stimulated phosphorylation of Akt was normal under these conditions. GLUT1 mRNA expression remained unchanged, whereas GLUT4 mRNA expression increased following azide treatment. In conclusion, under conditions of impaired mitochondrial respiration there was no evidence of impaired insulin signaling or glucose uptake following insulin exposure in this model system.

Published
2008

30. 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

38. 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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41. 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

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