| Title |
Progressive increase in mtDNA 3243A>G heteroplasmy causes abrupt transcriptional reprogramming
|
|---|---|
| Published in |
Proceedings of the National Academy of Sciences of the United States of America, September 2014
|
| DOI | 10.1073/pnas.1414028111 |
| Pubmed ID | |
| Authors |
Martin Picard, Jiangwen Zhang, Saege Hancock, Olga Derbeneva, Ryan Golhar, Pawel Golik, Sean O’Hearn, Shawn Levy, Prasanth Potluri, Maria Lvova, Antonio Davila, Chun Shi Lin, Juan Carlos Perin, Eric F. Rappaport, Hakon Hakonarson, Ian A. Trounce, Vincent Procaccio, Douglas C. Wallace |
| Abstract |
Variation in the intracellular percentage of normal and mutant mitochondrial DNAs (mtDNA) (heteroplasmy) can be associated with phenotypic heterogeneity in mtDNA diseases. Individuals that inherit the common disease-causing mtDNA tRNA(Leu(UUR)) 3243A>G mutation and harbor ∼10-30% 3243G mutant mtDNAs manifest diabetes and occasionally autism; individuals with ∼50-90% mutant mtDNAs manifest encephalomyopathies; and individuals with ∼90-100% mutant mtDNAs face perinatal lethality. To determine the basis of these abrupt phenotypic changes, we generated somatic cell cybrids harboring increasing levels of the 3243G mutant and analyzed the associated cellular phenotypes and nuclear DNA (nDNA) and mtDNA transcriptional profiles by RNA sequencing. Small increases in mutant mtDNAs caused relatively modest defects in oxidative capacity but resulted in sharp transitions in cellular phenotype and gene expression. Cybrids harboring 20-30% 3243G mtDNAs had reduced mtDNA mRNA levels, rounded mitochondria, and small cell size. Cybrids with 50-90% 3243G mtDNAs manifest induction of glycolytic genes, mitochondrial elongation, increased mtDNA mRNA levels, and alterations in expression of signal transduction, epigenomic regulatory, and neurodegenerative disease-associated genes. Finally, cybrids with 100% 3243G experienced reduced mtDNA transcripts, rounded mitochondria, and concomitant changes in nuclear gene expression. Thus, striking phase changes occurred in nDNA and mtDNA gene expression in response to the modest changes of the mtDNA 3243G mutant levels. Hence, a major factor in the phenotypic variation in heteroplasmic mtDNA mutations is the limited number of states that the nucleus can acquire in response to progressive changes in mitochondrial retrograde signaling. |
X Demographics
The data shown below were collected from the profiles of 11 X users who shared this research output. Click here to find out more about how the information was compiled.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| United States | 2 | 18% |
| Afghanistan | 1 | 9% |
| France | 1 | 9% |
| Australia | 1 | 9% |
| United Kingdom | 1 | 9% |
| Unknown | 5 | 45% |
Demographic breakdown
| Type | Count | As % |
|---|---|---|
| Members of the public | 7 | 64% |
| Scientists | 4 | 36% |
Mendeley readers
The data shown below were compiled from readership statistics for 252 Mendeley readers of this research output. Click here to see the associated Mendeley record.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| United States | 2 | <1% |
| Korea, Republic of | 1 | <1% |
| Russia | 1 | <1% |
| France | 1 | <1% |
| Unknown | 247 | 98% |
Demographic breakdown
| Readers by professional status | Count | As % |
|---|---|---|
| Student > Ph. D. Student | 59 | 23% |
| Researcher | 52 | 21% |
| Student > Bachelor | 25 | 10% |
| Student > Master | 21 | 8% |
| Other | 12 | 5% |
| Other | 42 | 17% |
| Unknown | 41 | 16% |
| Readers by discipline | Count | As % |
|---|---|---|
| Agricultural and Biological Sciences | 68 | 27% |
| Biochemistry, Genetics and Molecular Biology | 65 | 26% |
| Medicine and Dentistry | 28 | 11% |
| Neuroscience | 10 | 4% |
| Psychology | 4 | 2% |
| Other | 20 | 8% |
| Unknown | 57 | 23% |
Attention Score in Context
This research output has an Altmetric Attention Score of 43. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 10 January 2018.
All research outputs
#926,756
of 24,625,114 outputs
Outputs from Proceedings of the National Academy of Sciences of the United States of America
#14,628
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Outputs of similar age
#9,470
of 243,528 outputs
Outputs of similar age from Proceedings of the National Academy of Sciences of the United States of America
#245
of 914 outputs
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