Role of the creatine/phosphocreatine system in the regulation of mitochondrial respiration
Abstract
The mechanism of metabolic regulation of mitochondrial respiration in cardiac muscle cells was studied experimentally in the permeabilized heart fibres of mice and by computer modelling in silico. The experiments showed that the rate of mitochondrial respiration could be controlled by local production of ADP by mitochondrial creatine kinase in the intermembrane space of mitochondria. The spatially inhomogenous reaction-diffusion model of compartmentalized energy transfer was used to analyse which metabolite level in cytoplasm may be important for regulation of respiration. At low and moderate workloads, up to VO2 equal to 70 micromol min-1 g-1 dry weight, the only factor to which respiration responded was inorganic phosphate. At the values of VO2 higher than 70 micromol min-1 g-1 dry weight, the respiration rate responded mostly to changes in creatine, phosphocreatine and then time-averaged (over the contractile cycle) ADP concentrations in the cytoplasm. These results are taken to show that under conditions of moderate workloads, creatine kinase activity at given physiological creatine and phosphocreatine concentrations (apparent maximal activity achievable under these conditions) is in excess to oxidative phosphorylation rate, which is controlled by Pi concentration changes starting from very low values of the latter. At higher workloads mi-CK should be upregulated by increasing creatine and decreasing phosphocreatine concentrations, and only at very high workloads the ADP diffusion flux should be increased to upregulate oxidative phosphorylation. Thus, on the basis of the study in silico of compartmentalized energy transfer by phophocreatine/creatine system, the authors conclude that there exist multiple parallel regulatory factors controlling the rate of oxygen consumption in dependence of the workload. If creatine kinase is inhibited (and there is no myokinase activity), respiration requires high diffusive flux of ADP back into mitochondria, which is the sole regulator of respiration. This needs, however, increased ADP concentrations in the cytoplasm, which in turn result in inhibition of contraction.
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Higher doses of creatine supplementation may not be required to optimize brain creatine content and ATP (re)synthesis by mitochondrial creatine kinases.
“As such, higher doses of creatine supplementation may not be required to optimize brain creatine content4,5 and ATP (re)synthesis by mitochondrial creatine kinases.46”
From Effects of creatine supplementation on memory in healthy individuals: a systematic review and meta-analysis of randomized controlled trials (2023) · cites this paper as [46]
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- Authors
- Saks, V. A., Kongas, O., Vendelin, M., & Kay, L.
- Affiliations
- Université Joseph Fourier (FR)
- National Institute of Chemical Physics and Biophysics (EE)
- Corresponding author
- Saks, V.A.
- ORCID
- Vendelin, M.
- Venue
- Acta Physiologica Scandinavica
- Publisher
- Wiley
- Published
- 2000-04
- Volume
- 168
- Issue
- 4
- Pages
- 635-641
- ISSN
- 0001-6772 (ISSN-L)
- 1365-201X
- OpenAlex
- W2126652340
- Cited by
- 97
- References
- 20
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 2 · 2023: 1 · 2022: 5 · 2021: 2 · 2020: 5 · 2019: 3 · 2018: 3 · 2017: 2 · 2016: 3 · 2015: 3 · 2014: 3 · 2013: 3 · 2012: 3
- FWCI
- 1.68
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Acta Physiologica Scandinavica (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Function and Risk Factors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- creatine kinase, phosphocreatine, creatine, mitochondrial respiration, oxidative phosphorylation, ADP, inorganic phosphate, myocardium, reaction-diffusion systems, oxygen consumption, workload, adenylate kinase, computer modelling
- MeSH terms
- Animals, Creatine, Creatine Kinase, Energy Metabolism, Mitochondria, Muscle, Myocardium, Myofibrils, Oxygen Consumption, Phosphocreatine, Mice
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