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Article: Progressive increase in mtDNA 3243A>G heteroplasmy causes abrupt transcriptional reprogramming

TitleProgressive increase in mtDNA 3243A>G heteroplasmy causes abrupt transcriptional reprogramming
Authors
KeywordsElectron microscopy
Epigenetic
Mitochondrial disease
MtDNA variant
RNA-Seq
Issue Date2014
Citation
Proceedings of the National Academy of Sciences, 2014, v. 111 n. 38, p. E4033-E4042 How to Cite?
AbstractVariation 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 approximately 10-30% 3243G mutant mtDNAs manifest diabetes and occasionally autism; individuals with approximately 50-90% mutant mtDNAs manifest encephalomyopathies; and individuals with approximately 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.
Persistent Identifierhttp://hdl.handle.net/10722/220478
ISSN
2023 Impact Factor: 9.4
2023 SCImago Journal Rankings: 3.737
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorPicard, M-
dc.contributor.authorZhang, J-
dc.contributor.authorHancock, S-
dc.contributor.authorDerbeneva, O-
dc.contributor.authorGolhar, R-
dc.contributor.authorGolik, P-
dc.contributor.authorO'Hearn, S-
dc.contributor.authorLevy, S-
dc.contributor.authorPotluri, P-
dc.contributor.authorLvova, M-
dc.contributor.authorDavila, A-
dc.contributor.authorLin, CS-
dc.contributor.authorPerin, JC-
dc.contributor.authorRappaport, EF-
dc.contributor.authorHakonarson, H-
dc.contributor.authorTrounce, IA-
dc.contributor.authorProcaccio, V-
dc.contributor.authorWallace, DC-
dc.date.accessioned2015-10-16T06:43:28Z-
dc.date.available2015-10-16T06:43:28Z-
dc.date.issued2014-
dc.identifier.citationProceedings of the National Academy of Sciences, 2014, v. 111 n. 38, p. E4033-E4042-
dc.identifier.issn0027-8424-
dc.identifier.urihttp://hdl.handle.net/10722/220478-
dc.description.abstractVariation 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 approximately 10-30% 3243G mutant mtDNAs manifest diabetes and occasionally autism; individuals with approximately 50-90% mutant mtDNAs manifest encephalomyopathies; and individuals with approximately 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.-
dc.languageeng-
dc.relation.ispartofProceedings of the National Academy of Sciences-
dc.subjectElectron microscopy-
dc.subjectEpigenetic-
dc.subjectMitochondrial disease-
dc.subjectMtDNA variant-
dc.subjectRNA-Seq-
dc.titleProgressive increase in mtDNA 3243A>G heteroplasmy causes abrupt transcriptional reprogramming-
dc.typeArticle-
dc.identifier.emailZhang, J: jzhang1@hku.hk-
dc.identifier.authorityZhang, J=rp01713-
dc.identifier.doi10.1073/pnas.1414028111-
dc.identifier.pmcidPMC4183335-
dc.identifier.scopuseid_2-s2.0-84907267817-
dc.identifier.hkuros255690-
dc.identifier.volume111-
dc.identifier.issue38-
dc.identifier.spageE4033-
dc.identifier.epageE4042-
dc.identifier.isiWOS:000341988200012-
dc.identifier.issnl0027-8424-

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