Turn up the power - pharmacological activation of mitochondrial biogenesis in mouse models
Open accessAbstract
The oxidative phosphorylation (OXPHOS) system in mitochondria is responsible for the generation of the majority of cellular energy in the form of ATP. Patients with genetic OXPHOS disorders form the largest group of inborn errors of metabolism. Unfortunately, there is still a lack of efficient therapies for these disorders other than management of symptoms. Developing therapies has been complicated because, although the total group of OXPHOS patients is relatively large, there is enormous clinical and genetic heterogeneity within this patient population. Thus there has been a lot of interest in generating relevant mouse models for the different kinds of OXPHOS disorders. The most common treatment strategies tested in these mouse models have aimed to up-regulate mitochondrial biogenesis, in order to increase the residual OXPHOS activity present in affected animals and thereby to ameliorate the energy deficiency. Drugs such as bezafibrate, resveratrol and AICAR target the master regulator of mitochondrial biogenesis PGC-1α either directly or indirectly to manipulate mitochondrial metabolism. This review will summarize the outcome of preclinical treatment trials with these drugs in mouse models of OXPHOS disorders and discuss similar treatments in a number of mouse models of common diseases in which pathology is closely linked to mitochondrial dysfunction. In the majority of these studies the pharmacological activation of the PGC-1α axis shows true potential as therapy; however, other effects besides mitochondrial biogenesis may be contributing to this as well.
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AICAR rescued mitochondrial function in mice deficient in cytochrome c oxidase and augmented exercise endurance in healthy animals in a PGC1α-dependent manner, even if they were untrained.
“AICAR also rescued mitochondrial function in mice deficient in cytochrome c oxidase and augmented exercise endurance in healthy animals in a PGC1α-dependent manner, even if they were untrained (255, 256).”
From Metabolic Flexibility as an Adaptation to Energy Resources and Requirements in Health and Disease (2018) · cites this paper as [255]
In insulin-deficient mice, bezafibrate improves impaired glucose metabolism by augmenting hepatic mitochondrial performance, suppressing hepatic inflammatory pathways, and improving insulin sensitivity.
“In insulin-deficient mice, bezafibrate improves impaired glucose metabolism by augmenting hepatic mitochondrial performance [reviewed in Komen and Thorburn (255)], suppressing hepatic inflammatory pathways, and improving insulin sensitivity (271).”
From Metabolic Flexibility as an Adaptation to Energy Resources and Requirements in Health and Disease (2018) · cites this paper as [255]
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- Authors
- Komen, J. C., & Thorburn, D. R.
- Affiliations
- Royal Children's Hospital (AU)
- Corresponding author
- Thorburn, D R
- ORCID
- Thorburn, D R
- Venue
- British Journal of Pharmacology
- Publisher
- Wiley
- Published
- 2014-03-28
- Volume
- 171
- Issue
- 8
- Pages
- 1818-1836
- ISSN
- 0007-1188 (ISSN-L)
- 1476-5381
- PMC
- PMC3976607
- OpenAlex
- W1903564790
- Cited by
- 149
- References
- 188
- Citations by year
- 2026: 7 · 2025: 12 · 2024: 13 · 2023: 6 · 2022: 13 · 2021: 15 · 2020: 17 · 2019: 13 · 2018: 17 · 2017: 11 · 2016: 8 · 2015: 11 · 2014: 6
- FWCI
- 0.78
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- British Journal of Pharmacology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Australian National Health and Medical Research Council
- Victorian Government�s Operational Infrastructure Support Program
- 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 › Physiology › Adipose Tissue and Metabolism
- Keywords
- mitochondrial biogenesis, PGC-1α, oxidative phosphorylation disorders, inborn errors of metabolism, bezafibrate, resveratrol, AICAR, mitochondrial dysfunction, mouse model, pharmacological activation, energy deficiency
- MeSH terms
- Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Resveratrol, Aminoimidazole Carboxamide, Animals, Bezafibrate, Disease Models, Animal, Energy Metabolism, Mitochondria, Ribonucleotides, Stilbenes, Transcription Factors, Up-Regulation, Mitochondrial Diseases, AMP-Activated Protein Kinases, Sirtuin 1, Mitochondrial Turnover
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