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Cited by 220Mitochondrial Function and PathologyMetabolism and Genetic DisordersCardiovascular Function and Risk Factors

A switch in metabolism precedes increased mitochondrial biogenesis in respiratory chain-deficient mouse hearts

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Hansson, Anna, Hance, Nicole, Dufour, Eric, Rantanen, Anja, Hultenby, Kjell, Clayton, David A., Wibom, Rolf, Larsson, Nils-Göran·2004·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.0308710100PMC PMC365756
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Abstract

We performed global gene expression analyses in mouse hearts with progressive respiratory chain deficiency and found a metabolic switch at an early disease stage. The tissue-specific mitochondrial transcription factor A ( Tfam ) knockout mice of this study displayed a progressive heart phenotype with depletion of mtDNA and an accompanying severe decline of respiratory chain enzyme activities along with a decreased mitochondrial ATP production rate. These characteristics were observed after 2 weeks of age and became gradually more severe until the terminal stage occurred at 10-12 weeks of age. Global gene expression analyses with microarrays showed that a metabolic switch occurred early in the progression of cardiac mitochondrial dysfunction. A large number of genes encoding critical enzymes in fatty acid oxidation showed decreased expression whereas several genes encoding glycolytic enzymes showed increased expression. These alterations are consistent with activation of a fetal gene expression program, a well-documented phenomenon in cardiac disease. An increase in mitochondrial mass was not observed until the disease had reached an advanced stage. In contrast to what we have earlier observed in respiratory chain-deficient skeletal muscle, the increased mitochondrial biogenesis in respiratory chain-deficient heart muscle did not increase the overall mitochondrial ATP production rate. The observed switch in metabolism is unlikely to benefit energy homeostasis in the respiratory chain-deficient hearts and therefore likely aggravates the disease. It can thus be concluded that at least some of the secondary gene expression alterations in mitochondrial cardiomyopathy do not compensate but rather directly contribute to heart failure progression.

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  • In a mouse model with progressive cardiomyopathy induced by tissue-specific Tfam knockout causing mtDNA depletion, gene expression studies demonstrated strong induction of LON-protease expression.

    “Gene expression studies in a mouse model with progressive cardiomyopathy, induced by tissue-specific Tfam knockout causing mtDNA depletion, has demonstrated a strong induction of LON-protease expression (14).”

    From Progressive parkinsonism in mice with respiratory-chain-deficient dopamine neurons (2007) · cites this paper as [14]

  • Mouse models with decreased mtDNA expression have increased cell death with little or no increase of oxidative stress.

    “We have studied a variety of mouse models with decreased mtDNA expression (10, 12–18) and such mice have increased cell death with little or no increase of oxidative stress (18, 30).”

    From Progressive parkinsonism in mice with respiratory-chain-deficient dopamine neurons (2007) · cites this paper as [14]

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Authors
Hansson, A., Hance, N., Dufour, E., Rantanen, A., Hultenby, K., Clayton, D. A., Wibom, R., & Larsson, N.-G.
Affiliations
  • Karolinska University Hospital (SE)
  • Departments of Medical Nutrition and Biosciences and Laboratory Medicine and Clinical Research Center, Karolinska Institutet, Novum, Karolinska University Hospital, S-141 86 Stockholm, Sweden; and Howard Hughes Medical Institute, 4000 Jones Bridge Road, Chevy Chase, MD 20815-6789
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2004-02-20
Volume
101
Issue
9
Pages
3136-3141
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.0308710100
PMC
PMC365756
OpenAlex
W2051694207
Cited by
220
References
37
Citations by year
2026: 4 · 2025: 9 · 2024: 5 · 2023: 9 · 2022: 8 · 2021: 9 · 2020: 8 · 2019: 8 · 2018: 6 · 2017: 17 · 2016: 7 · 2015: 10 · 2014: 6 · 2013: 7 · 2012: 19
FWCI
5.57
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
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
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Function and Risk Factors
Keywords
mitochondrial cardiomyopathy, respiratory chain deficiency, metabolic switch, mitochondrial biogenesis, TFAM, mtDNA depletion, fatty acid oxidation, glycolysis, mitochondrial ATP production, heart failure progression, cardiac gene expression
MeSH terms
Animals, Crosses, Genetic, DNA-Binding Proteins, Fatty Acids, Genotype, Glycolysis, High Mobility Group Proteins, Microscopy, Electron, Mitochondria, Heart, Cardiomyopathies, Myocardium, Transcription Factors, Mice, Knockout, Mitochondrial Diseases, Animals, Genetically Modified, Mice

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