Skeletal muscle gene expression profiling in mitochondrial disorders
Abstract
Extremely variable clinic and genetic features characterize mitochondrial encephalomyopathy (MEM). Pathogenic mitochondrial DNA (mtDNA) defects can be divided into large-scale rearrangements and single point mutations. Clinical manifestations become evident when a threshold percentage of the total mtDNA is mutated. In some MEM, the "mutant load" in an affected tissue is directly related to the severity of the phenotype. However, the clinical phenotype is not simply a direct consequence of the relative abundance of mutated mtDNA. Other factors, such as nuclear background, can contribute to the disease process, resulting in a wide range of phenotypes caused by the same mutation. Using Affymetrix oligonucleotide cDNA microarrays (HG-U133A), we studied the gene expression profile of muscle tissue biopsies obtained from 12 MEM patients [4 common 4977 bp deleted mtDNA and 8 A3243G: 4 progressive external ophthalmoplegia (PEO) and 4 mitochondrial myopathy, encephalopathy, lactic cidosis, and stroke-like episodes syndrome (MELAS) phenotypes] compared with age-matched healthy individuals. We found several differentially expressed genes: 35 were markedly up-regulated in the mtDNA macro-deletion group (vs. the control group) and 4 decreased; 56 genes were dysregulated in A3243G-related disorders (53 down-regulated in PEO and 3 up-regulated in MELAS). Finally, 12 genes were similarly regulated in the majority of the MEM patients under study. Amongst these, we identified an increased expression of genes related to the metabolism of the amino groups, as well as of several genes involved in genetic information processing. Moreover, few genes were similarly decreased in MEM patients vs. the control group. Real-time PCR demonstrated excellent reproducibility of the microarray-based findings. The observed expression changes are likely to represent a molecular signature for mitochondrial disorders. Furthermore, the differential expression profile of MELAS(A3243G) vs. PEO(A3243G) may support a role of nuclear background in contributing to these different clinical phenotypes. MEM microarray data are available from GEO database (http://www.ncbi.nlm.nih.gov/geo/) with the accession number: GSE1462.
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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 [211]
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Mitochondrial DNA mutations and human disease
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“An induction in the expression of several nuclear RC transcripts has also been observed in macrodeleted muscle [211] and in 143B cells harbouring the m.”
BackgroundMitochondrial myopathy induces a starvation-like response
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- Authors
- Crimi, M., Bordoni, A., Menozzi, G., Riva, L., Fortunate, F., Galbiati, S., Del Bo, R., Pozzoli, U., Bresolin, N., & Comi, G. P.
- Affiliations
- University of Milan (IT)
- IRCCS Eugenio Medea (IT)
- Department of Neurological Sciences University of Milan 20122 Milan
- Venue
- The FASEB Journal
- Publisher
- Wiley
- Published
- 2005-02-23
- Volume
- 19
- Issue
- 7
- Pages
- 1-30
- ISSN
- 0892-6638 (ISSN-L)
- 1530-6860
- OpenAlex
- W2139917614
- Cited by
- 56
- References
- 57
- Citations by year
- 2025: 1 · 2024: 2 · 2023: 2 · 2020: 1 · 2019: 3 · 2018: 2 · 2017: 2 · 2016: 2 · 2015: 2 · 2014: 6 · 2013: 6 · 2012: 2
- FWCI
- 1.38
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The FASEB Journal (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Ministero della Salute
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Keywords
- mitochondrial encephalomyopathy, skeletal muscle gene expression, mitochondrial DNA deletions, A3243G mutation, MELAS, chronic progressive external ophthalmoplegia, nuclear background, phenotypic variability, gene expression signatures
- MeSH terms
- Adolescent, Adult, Biopsy, DNA, Mitochondrial, Female, Gene Expression Regulation, Humans, Male, Middle Aged, Mutation, Phenotype, RNA, Messenger, Reproducibility of Results, Mitochondrial Encephalomyopathies, MELAS Syndrome, Gene Deletion, Muscle, Skeletal, Gene Dosage, Reverse Transcriptase Polymerase Chain Reaction, Oligonucleotide Array Sequence Analysis, Gene Expression Profiling
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