Mitochondrial myopathy induces a starvation-like response
Abstract
Mitochondrial respiratory chain (RC) deficiency is among the most common causes of inherited metabolic disease, but its physiological consequences are poorly characterized. We studied the skeletal muscle gene expression profiles of mice with late-onset mitochondrial myopathy. These animals express a dominant patient mutation in the mitochondrial replicative helicase Twinkle, leading to accumulation of multiple mtDNA deletions and progressive subtle RC deficiency in the skeletal muscle. The global gene expression pattern of the mouse skeletal muscle showed induction of pathways involved in amino acid starvation response and activation of Akt signaling. Furthermore, the muscle showed induction of a fasting-related hormone, fibroblast growth factor 21 (Fgf21). This secreted regulator of lipid metabolism was also elevated in the mouse serum, and the animals showed widespread changes in their lipid metabolism: small adipocyte size, low fat content in the liver and resistance to high-fat diet. We propose that RC deficiency induces a mitochondrial stress response, with local and global changes mimicking starvation, in a normal nutritional state. These results may have important implications for understanding the metabolic consequences of mitochondrial myopathies.
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The deletor mouse is a PEO mouse model because its phenotype is strikingly similar to PEO patients.
“The phenotype of the deletor mouse is strikingly similar to PEO patients, thus creating a PEO mouse model (Tyynismaa et al., 2010).”
From Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases (2017) · cites this paper as Tyynismaa et al., 2010
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- Authors
- Tyynismaa, H., Carroll, C. J., Raimundo, N., Ahola-Erkkilä, S., Wenz, T., Ruhanen, H., Guse, K., Hemminki, A., Peltola-Mjøsund, K. E., Tulkki, V., Orešič, M., Moraes, C. T., Pietiläinen, K., Hovatta, I., & Suomalainen, A.
- Affiliations
- University of Miami (US)
- Helsinki University Hospital (FI)
- University of Helsinki (FI)
- Corresponding author
- Suomalainen, Anu
- ORCID
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2010-07-23
- Volume
- 19
- Issue
- 20
- Pages
- 3948-3958
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2138707492
- Cited by
- 300
- References
- 38
- Citations by year
- 2026: 8 · 2025: 15 · 2024: 22 · 2023: 17 · 2022: 29 · 2021: 24 · 2020: 21 · 2019: 17 · 2018: 24 · 2017: 25 · 2016: 23 · 2015: 23 · 2014: 17 · 2013: 20 · 2012: 8
- FWCI
- 4.56
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed (publishedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion)
- STM:n Hallinnonalan avoin julkaisuarkisto (Julkari) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Keywords
- mitochondrial myopathy, mitochondrial respiratory chain deficiency, Twinkle helicase, mitochondrial DNA deletions, skeletal muscle gene expression, Akt signaling, FGF21, lipid metabolism, adipocyte size, mitochondrial stress response, inborn errors of metabolism
- MeSH terms
- Amino Acids, Animals, Base Sequence, DNA Helicases, DNA, Mitochondrial, Electron Transport, Fibroblast Growth Factors, Gene Expression Regulation, Methylenetetrahydrofolate Dehydrogenase (NADP), Mice, Transgenic, Mitochondria, Muscle, Starvation, Stress, Physiological, Gene Expression, Polymerase Chain Reaction, Mitochondrial Myopathies, Sequence Deletion, Adipocytes, Muscle, Skeletal, Gene Expression Profiling, Mitochondrial Proteins, Lipid Metabolism, Proto-Oncogene Proteins c-akt, Mice
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