ArticlePloS one2012
Mitochondrial DNA maintenance is regulated in human hepatoma cells by glycogen synthase kinase 3β and p53 in response to tumor necrosis factor α.
Article in PloS one, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 26 citations in OpenAlex.
- Concordance of cancer-associated cytokines and mitochondrial DNA deletions in individuals with hepatocellular carcinoma and people living with HIV in Ghana.BMC gastroenterology · 2025Article
- Genetic interaction between oxidative stress and body mass index in a Spanish population.Redox biology · 2025Article
- Mitochondrial DNA-targeted therapy: A novel approach to combat cancer.Cell insight · 2023Review
- Maternal Inflammation During Pregnancy and Offspring Brain Development: The Role of Mitochondria.Biological psychiatry. Cognitive neuroscience and neuroimaging · 2022Review
- Glycogen synthesis and beyond, a comprehensive review of GSK3 as a key regulator of metabolic pathways and a therapeutic target for treating metabolic diseases.Medicinal research reviews · 2022Review
- N-Acetylcysteine Reduces miR-146a and NF-κB p65 Inflammatory Signaling Following Cadmium Hepatotoxicity in Rats.Biological trace element research · 2021Article
- Stereochemical and structural effects of (2R,6R)-hydroxynorketamine on the mitochondrial metabolome in PC-12 cells.Biochimica et biophysica acta. General subjects · 2018Article
- Increased expression of mitochondrial transcription factor A and nuclear respiratory factor-1 predicts a poor clinical outcome of breast cancer.Oncology letters · 2018Article
- Arachidonyl-2-Chloroethylamide Alleviates Cerebral Ischemia Injury Through Glycogen Synthase Kinase-3β-Mediated Mitochondrial Biogenesis and Functional Improvement.Molecular neurobiology · 2017Article
- The little big genome: the organization of mitochondrial DNA.Frontiers in bioscience (Landmark edition) · 2017Review
- Commentary: Mitochondrial DNA damage and loss in diabetes.Diabetes/metabolism research and reviews · 2016Article
- A splice variant of the human ion channel TRPM2 modulates neuroblastoma tumor growth through hypoxia-inducible factor (HIF)-1/2α.The Journal of biological chemistry · 2014Article
- Interleukin-1β causes excitotoxic neurodegeneration and multiple sclerosis disease progression by activating the apoptotic protein p53.Molecular neurodegeneration · 2014Article
- Screen for mitochondrial DNA copy number maintenance genes reveals essential role for ATP synthase.Molecular systems biology · 2014Article
- Luminol-based chemiluminescent signals: clinical and non-clinical application and future uses.Applied biochemistry and biotechnology · 2014Review
- Article
- GSK-3 and mitochondria in cancer cells.Frontiers in oncology · 2013Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
8 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
During chronic liver inflammation, up-regulated Tumor Necrosis Factor alpha (TNF-α) targets hepatocytes and induces abnormal reactive oxygen species (ROS) production responsible for mitochondrial DNA (mtDNA) alterations. The serine/threonine Glycogen Synthase Kinase 3 beta (GSK3β) plays a pivotal role during inflammation but its involvement in the maintenance of mtDNA remains unknown. The aim of this study was to investigate its involvement in TNF-α induced mtDNA depletion and its interrelationship with p53 a protein known to maintain mtDNA copy numbers. Using quantitative polymerase chain reaction (qPCR) we found that at 30 min in human hepatoma HepG2 cells TNF-α induced 0.55±0.10 mtDNA lesions per 10 Kb and a 52.4±2.8% decrease in mtDNA content dependent on TNF-R1 receptor and ROS production. Both lesions and depletion returned to baseline from 1 to 6 h after TNF-α exposure. Luminol-amplified chemiluminescence (LAC) was used to measure the rapid (10 min) and transient TNF-α induced increase in ROS production (168±15%). A transient 8-oxo-dG level of 1.4±0.3 ng/mg DNA and repair of abasic sites were also measured by ELISA assays. Translocation of p53 to mitochondria was observed by Western Blot and co-immunoprecipitations showed that TNF-α induced p53 binding to GSK3β and mitochondrial transcription factor A (TFAM). In addition, mitochondrial D-loop immunoprecipitation (mtDIP) revealed that TNF-α induced p53 binding to the regulatory D-loop region of mtDNA. The knockdown of p53 by siRNAs, inhibition by the phosphoSer(15)p53 antibody or transfection of human mutant active GSK3βS9A pcDNA3 plasmid inhibited recovery of mtDNA content while blockade of GSK3β activity by SB216763 inhibitor or knockdown by siRNAs suppressed mtDNA depletion. This study is the first to report the involvement of GSK3β in TNF-α induced mtDNA depletion. We suggest that p53 binding to GSK3β, TFAM and D-loop could induce recovery of mtDNA content through mtDNA repair.
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