ArticleProceedings of the National Academy of Sciences of the United States of America2014
Progressive increase in mtDNA 3243A>G heteroplasmy causes abrupt transcriptional reprogramming.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 193 papers, 4 of them syntheses that pooled it.
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Who cites it
193 citing papers in PubMed, 4 syntheses or guidelines pooled it, 297 citations in OpenAlex.
- Stress and circulating cell-free mitochondrial DNA: A systematic review of human studies, physiological considerations, and technical recommendations.Mitochondrion · 2021Pooled it
- The Spectrum of Mitochondrial Ultrastructural Defects in Mitochondrial Myopathy.Scientific reports · 2016Pooled it
- Mitochondrial Aspartate/Glutamate Carrier SLC25A12 and Autism Spectrum Disorder: a Meta-Analysis.Molecular neurobiology · 2016Pooled it
- Psychological Stress and Mitochondria: A Systematic Review.Psychosomatic medicinePooled it
- Beta-adrenergic blockade blunts inflammatory and antiviral/antibody gene expression responses to acute psychosocial stress.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2021Trial
- Low frequency mitochondrial DNA heteroplasmy SNPs in blood, retina, and [RPE+choroid] of age-related macular degeneration subjects.PloS one · 2021Trial
- The causal pathway effects of a physical activity intervention on adiposity in children: The KISS Study cluster randomized clinical trial.Scandinavian journal of medicine & science in sports · 2020Trial
- Mitochondrial DNA homeostasis: A novel therapeutic target for neurodegenerative diseases.Neural regeneration research · 2026Article
- Cross-species urinary metabolomics identifies 2-hydroxyisovalerate as a candidate biomarker for mtDNA-based disorders.Metabolomics : Official journal of the Metabolomic Society · 2026Article
- Mitochondrial OXPHOS restricts SARS-CoV-2 replication.Science advances · 2026Article
- Mitochondrial retrograde signaling in gastric cancer: mtDNA mutations, ROS-driven NF-κB/HIF-1α activation, and Warburg effect amplification.Frontiers in physiology · 2026Review
- Clinical Validation of Digital PCR for Precise m.3243A>G Heteroplasmy Quantification in Early-Onset Diabetes.Journal of diabetes research · 2026Article
- A systems genetics approach to uncover mitochondrial drivers of heart failure reveals mitochondria-nuclear cross talk in genetically diverse mouse strains.bioRxiv : the preprint server for biology · 2025Article
- Partial restoration of mitochondrial dysfunction by AAV-Ant1 protects from dilated cardiomyopathy in Ant1Nature communications · 2025Article
- The allostatic triage model of psychopathology (ATP Model): How reallocation of brain energetic resources under stress elicits psychiatric symptoms.Neuroscience and biobehavioral reviews · 2025Review
- Mitochondrial DNA Replication and Disease: A Historical Perspective on Molecular Insights and Therapeutic Advances.International journal of molecular sciences · 2025Review
- Somatic mtDNA mutations at intermediate levels of heteroplasmy are a source of functional heterogeneity among primary leukemic cells.Science advances · 2025Article
- Rewriting nuclear epigenetic scripts in mitochondrial diseases as a strategy for heteroplasmy control.EMBO molecular medicine · 2025Article
- A review of the link between the lactate-GPR81 axis and mitochondrial angiopathy in MELAS based on imaging characteristics.Journal of neurology · 2025Review
- Article
133 more citing papers are in PubMed but not listed here.
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Authors and funding
18 authors at 9 institutions in 6 countries.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.