CHOP (C/EBP homologous protein) and ASNS (asparagine synthetase) induction in cybrid cells harboring MELAS and NARP mitochondrial DNA mutations
Abstract
Mitochondrial dysfunction caused by mutations in mitochondrial DNA (mtDNA) is related to a variety of diseases including MELAS and NARP syndromes. However, little is known about the intracellular responses induced by mtDNA mutations. In order to identify genes whose expression is altered as a result of the presence of mtDNA mutations, DNA microarray analysis was performed using human 143B osteosarcoma cells harboring 3243A>G [tRNA-Leu (UUR)] and 8993T>G [ATPase6 Leu156Arg] mtDNA mutations associated with MELAS and NARP syndromes (2SD and NARP3-1 cybrid cells), respectively. We found that mRNA and protein levels of ATF4, CHOP and ASNS were upregulated in 2SD and NARP3-1 cells as compared with parental cells. Reporter assays demonstrated that transcription of CHOP and ASNS genes was upregulated through the AARE (amino acid regulatory element) and NSRE-1 (nutrient-sensing response element-1) enhancer elements to which ATF4 binds, respectively. Furthermore, knockdown of ATF4 by RNA interference reduced CHOP and ASNS transcription in 2SD and NARP3-1 cells. These results suggest that the presence of mtDNA mutations elicits upregulation of CHOP and ASNS genes through the elevation of ATF4 expression and its binding to the AARE and NSRE-1, respectively.
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Genes involved in cellular metabolic pathways (TCA cycle, energy production, amino acid metabolism) are up-regulated in various models with mtDNA mutations (4977 bp macrodeletion, LHON m.3460G N A and m.11778G N A, m.8993T N G NARP, m.3243A N G).
“For example, genes involved in cellular metabolic pathways, such as the TCA cycle, energy production, and amino acid metabolism, are reportedly up-regulated not only in patients with the 4977 bp macrodeletion [211], but also in two lymphoblast cybrid cells containing the LHON mutations m.3460G N A (in the MT-ND1 gene) and m.11778G N A (MT-ND4 gene) [158], in a 143B osteosarcoma cybrid cell line”
From Mitochondrial DNA mutations and human disease (2010) · cites this paper as [212]
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Mitochondrial DNA mutations and human disease
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“8993TNG NARP mutation [212].”
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GDF15 is a novel biomarker to evaluate efficacy of pyruvate therapy for mitochondrial diseases
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- Authors
- Fujita, Y., Ito, M., Nozawa, Y., Yoneda, M., Oshida, Y., & Tanaka, M.
- Affiliations
- Nagoya University (JP)
- University of Fukui (JP)
- Research Center of Health, Physical Fitness and Sports, Nagoya University (JP)
- Tokyo Metropolitan Institute of Gerontology (JP)
- Corresponding author
- Ito, Masafumi
- Venue
- Mitochondrion
- Publisher
- Elsevier BV
- Published
- 2007-02
- Volume
- 7
- Issue
- 1-2
- Pages
- 80-88
- ISSN
- 1567-7249 (ISSN-L)
- OpenAlex
- W2072635838
- Cited by
- 34
- References
- 49
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 1 · 2023: 2 · 2022: 2 · 2020: 3 · 2018: 2 · 2016: 1 · 2015: 4 · 2014: 3 · 2013: 4 · 2012: 2
- FWCI
- 0.68
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Mitochondrion (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Ministry of Health, Labour and Welfare
- Ministry of Education, Culture, Sports, Science and Technology (17A-10)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
- Keywords
- CHOP, asparagine synthetase, ATF4, mitochondrial DNA mutations, MELAS, NARP syndrome, cybrid cells, 3243A>G mutation, mitochondrial dysfunction
- MeSH terms
- Antioxidants, Aspartate-Ammonia Ligase, Ataxia, DNA, Mitochondrial, Humans, Hybrid Cells, Peripheral Nervous System Diseases, Retinitis Pigmentosa, Rotenone, Osteosarcoma, Syndrome, Tumor Cells, Cultured, Up-Regulation, MELAS Syndrome, Oligonucleotide Array Sequence Analysis, Mitochondrial Diseases, RNA Interference, Activating Transcription Factor 4, Transcription Factor CHOP
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